## Ernst Schering prize lecture by Feldmann and Maini

Yesterday Sir Marc Feldmann and Sir Ravinder Maini from Imperial College were awarded the Ernst Schering prize in recognition of their development of the monoclonal antibody infliximab as a therapy for rheumatoid arthritis. In fact, as far as I know, this was the first therapy of this type to be used for any autoimmune disease. Today they gave a corresponding lecture at the Charite in Berlin and I was fortunate enough to be able to attend. A remarkable aspect of their achievement is that they were intimately involved in the whole process from a theory of Feldmann concerning the mechanism of autoimmune diseases to seeing the drug through clinical testing. One point which was mentioned several times by them and others was that this kind of development would probably be impossible today due to EU regulations. They showed a film clip in black and white of one of the first patients they treated with the new method, a young woman. First she was shown before the therapy coming down stairs with great difficulty, clinging to the banister. Then whe was shown a few weeks later, after the therapy, running, or almost skipping, down the same stairs, a picture of health. It was pointed out that she was not a typical patient since she was young and she had only had RA for a relatively short time before therapy. Interestingly, the initial trials of this drug were done on a ‘single-blind’ basis. The use of this type of drug was so new that it was considered too risky for the doctors doing the treatment not to know who was getting treated so that their state could be monitored closely. I noted on one transparency that it was written that the patients were treated sequentially. This made me think involuntarily of the recent disaster with the trials of one drug where care was not taken to start giving the drug to different patients after a long enough time interval. Infliximab and other antibodies against tumour necrosis factor $\alpha$, alone or in combination with methotrexate have revolutionized the treatment of RA. The disease cannot be cured, but its progression can be stopped. A picture was shown of one older woman, evidently moving forward with great difficulty with a walking frame and with her body very deformed by the disease. The comment from one of the speakers was that this is something which is no longer seen in clinics. The importance of these drugs can be seen by the fact that 15 billion per year is spent on them.

The lecture also generated some mathematical thoughts in me. In the early days of these developments knowledge was available about various cytokines in the joints of patients with RA. Feldmann described the special role of TNF$\alpha$ as being the rate-limiting step. This conjured up for me a picture of a dynamical system describing the concentrations of various cytokines, with one of the variables describing TNF$\alpha$. What is its special role in comparison with, for instance, IL1 which had previously been believed to be of central significance? The data say that administering antibodies to TNF$\alpha$ leads to a fall in the concentration of IL1 and various other cytokines, both inflammatory and anti-inflammatory. On the other hand, administering an antibody to IL1 does not lead to a significant decrease in the concentration of TNF$\alpha$. How can we think of this in terms of the dynamical system? An antibody can function as a knockout – it effectively sets the coefficient in front of the terms describing the production of the corresponding antigen to zero. Then the hyperplane where its concentration vanishes becomes invariant and carries a new dynamical system. The original system has a stationary solution where all concentrations are positive. The knockout system has a similar stationary solution and the question is how the concentration of a given substance compares in the two cases. Later on in the talk there was discussion of finding other substances upstream of TNF$\alpha$ as a basis for new therapies. What does that mean? Intuitively if $X$ is upstream of $Y$ it means that the production of $X$ causes the production of $Y$. A symptom of this could be that a knockout of $X$ leads to a decrease of $Y$. Thus what is special about TNF$\alpha$ is that it is far upstream.

I was very impressed by the achievements of the two speakers and by the account they gave of their work. It was also clear that they are very active in pushing these ideas further. Might they get a Nobel prize sometime soon? I for one would not be sorry if they did.