THE drug involved in the trial that resulted in six volunteers becoming critically ill is designed to activate the killer cells of the immune system. TGN1412 appears to have done so in this case to spectacularly damaging effect.

It belongs to a class of biological agents known as monoclonal antibodies (MABs), which were discovered at Cambridge in the mid-1970s in research that won a share of the 1984 Nobel Prize for César Milstein and George Köhler. MABs are pure antibodies that can be produced in large amounts outside the body.

Normally, antibodies are produced in the body in response to infection. They seek out the germs responsible and help to destroy them. MABs, by contrast, are laboratory products.

The first thought was that they could be used to boost the body’s own response to disease, but that proved difficult. More recently, greater success has been achieved by making MABs that work on a specific part of the immune system and modify its effects, or that carry drugs or radioactive materials to specific sites in the body.

MABs of this kind can be used to treat auto-immune diseases, in which the body’s immune system attacks itself. Rheumatoid arthritis is a classic example.

TeGenero, which developed TGN1412, call it a SuperMAB because it is capable of activating the killer T cells especially powerfully. Normally, these killer cells need two signals to get them started, one of which is stimulation of a receptor on the T cells called TCR (the T-cell antigen receptor).

Experiments published in the Journal of Experimental Medicine in 2003 show that TGN1412 can activate the killer cells while bypassing the TCR. This made the product more potent and more widely useful, the company said at the time.

TGN1412 works by activating another receptor, CD28. The paper, co-authored by the discoverer of TGN1412, Thomas Hünig, of the University of Würzberg, suggests that antibodies with this property may be “useful for the development of T cell stimulatory drugs”.

Last year TGN1412 was given “orphan drug status” by the European Medicines Agency as a possible cancer treatment. The thinking was that by stimulating the immune response, patients with a form of leukaemia might be able to eliminate the cancer cells themselves.

Normally, the immune response does not deal effectively with cancer, because it lacks power or does not recognise the cancer cells as foreign so does not attack them. In B-cell chronic lymphocytic leukaemia, the cancer is linked to dysfunctional T cells. So by boosting them TeGenero hoped that better control of the disease might be achieved. Winning orphan drug status provides various financial advantages for the manufacturers.

TeGenero says that the effects found in the trial do not reflect what happened in laboratory studies. From this it can be inferred that animals tested with the drug did not show the violent enhancement of the immune system apparently seen in the human volunteers.

“In pre-clinical studies, TGN1412 has been shown to be safe and the reactions which occurred in these volunteers were completely unexpected,” Thomas Hanke, chief scientific officer of TeGenero, said.

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