THE full clinical details of what happened to six men given a new antibody in a disastrous drug trial have been revealed by the doctors who saved their lives. But far from explaining how the drug caused multiple organ failure, the results just add to the confusion.
Alongside the details, published in the New England Journal of Medicine this week, are suggestions as to why the men reacted so badly when the mice showed no ill effects. They include the possibility that it simply works differently in people and mice, and speculation that the sterile conditions in which the mice were bred may have mitigated its effects.
On the morning of 13 March, the TGN1412 antibody was injected directly into the blood of the six volunteers at a UK hospital by Parexel. This firm was managing the trial on behalf of TeGenero of W眉rzburg in Germany, which developed the drug to treat rheumatoid arthritis and other autoimmune disorders.
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The men received doses 500 times smaller than those used in animals. In mice, the antibody triggered the multiplication of T-cells. A subset called regulatory T-cells multiplied the fastest, which calmed the animals鈥� immune systems 鈥� an effect the drug鈥檚 designers hoped could be exploited to ease the symptoms of rheumatoid arthritis, in which T-cells attack the body鈥檚 own tissues.
Just 60 to 90 minutes after the volunteers were injected, the opposite happened. The drug made their bodies produce massive amounts of inflammatory chemicals called cytokines, which usually combat severe infections such as blood poisoning. Such high levels were produced that all six men quickly began to suffer excruciating headaches, shivering, back and gut pain, diarrhoea, swelling and nausea. Within 4 hours, each had a fever, their blood pressure had dropped and their hearts were racing. After another hour one patient had breathing difficulties and all had pain in the lungs.
At this point, the volunteers were given steroids and other medications to ease the inflammation. However, 12 hours later the patient struggling to breathe had to be put on a ventilator in intensive care. 鈥淏y 24 hours we had two people on ventilators and the four others needing support with breathing,鈥� says Ganesh Suntharalingam, head of the team that cared for the men in the intensive care unit of London鈥檚 Northwick Park hospital. Within two days, all had suffered multiple organ failure, although a day later the four least-affected patients began to show signs of recovery (DOI: 10.1056/NEJMoa063842).
One of the main mysteries is why levels of white blood cells collapsed, something not seen in animals. 鈥淚t was the opposite of what we expected,鈥� says Nicki Panoskaltsis, co-author and haematologist on the team. 鈥淭-cells and monocytes went down in the first 8 hours to zero,鈥� she says. 鈥淥ne would have expected expansion, not complete depletion.鈥�
It might be that rather than disappearing, the white blood cells congregated in the lymph nodes and spleen, though neither was enlarged in the volunteers. Nor is it clear what caused the cytokine storm. 鈥淚t鈥檚 for expert groups investigating for the UK Department of Health to find out,鈥� says Panoskaltsis.
In an accompanying commentary in the same journal, immunologists propose explanations for the differing effects in animals and humans. One is that TGN1412 bound to and interfered with the CD28 receptor it targets much more strongly in humans than animals, with correspondingly more dramatic results (DOI: 10.1056/NEJMpo68087).
Another possibility is that T-cells were harder to activate in the mice because they were bred in sterile conditions. Such T-cells might not be programmed to target specific pathogens, which means they would be likely to respond less strongly than the volunteers鈥� T-cells, which have encountered myriad pathogens before.
鈥淚n mice the antibody calmed the immune system, but in the volunteers the opposite happened鈥�
