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Kiel scientists are analysing the effects and side-effects of various new developments
The body's own messenger Interleukin-6 is a promising target for the treatment of inflammatory diseases, but also important for defence against pathogens and for tissue regeneration. In a current publication in Nature Reviews Drug Discovery, Kiel biochemists from the Cluster of Excellence "Inflammation at Interfaces", together with a team from Munich, give an overview of the role the cytokine plays in health and disease. Their work includes analysing the various ways to suppress the signals of Interleukin-6, and what consequences this has.
The cytokine Interleukin-6 (IL-6) is of central importance for the inflammation process, and amongst other things, has also been identified as the driving force behind rheumatic diseases. Various newly-developed drugs aim to inhibit the signals of this messenger substance. Two of them have already been approved for treating rheumatism: Tocilizumab (since 2009) and Sarilumab (since 2017). 16 therapeutics for various areas of application are currently in clinical trials. The drugs that are already available, as well as some other new developments, inhibit the signal transmission via the IL-6 receptor in the cell membrane. “This signal path is restricted to cells that carry an IL-6 receptor. But these are only a few cell types, in particular immune cells and liver cells," explained Professor Stefan Rose-John from the Institute of Biochemistry at Kiel University, and board member of the Cluster of Excellence "Inflammation at Interfaces". "This approach works and is an alternative treatment option for patients," added his colleague Dr Christoph Garbers. However, blocking the IL-6 receptor also suppresses the physiological functions of the messenger, such as fighting pathogens and regenerating tissue. Increased susceptibility to infections is therefore a known side-effect of the treatment.
When using a different approach, the selective blocking of the so-called trans-signalling pathway, this is not a problem. Here, IL-6 binds with the “soluble” IL-6 receptor found in the blood and in inflamed tissue. "In previous investigations into inflammations in joints and the bowel, as well as into the growth of cancer cells, it was determined that the disease-causing effects of Interleukin-6 are primarily conveyed via this signalling pathway," said Rose-John, who discovered this second pathway over 20 years ago. To date there is only one agent, which exclusively blocks this trans-signalling pathway selectively and effectively: the drug developed within the Cluster of Excellence, Olamkicept (sgp130Fc). It is currently in phase II of clinical trials for the treatment of people with chronic inflammatory bowel disease, after the safety of the substance was already demonstrated in phase I trials. Previously, the therapeutic benefits of the substance have already been demonstrated in many animal models. "The special thing about trans-signalling is that the complex of IL-6 and the soluble receptor can also trigger a signal on cells which don't have their own IL-6 receptor," explained the Kiel biochemist.
A further group of substances which interfere with the signalling of IL-6 are the Janus kinase (JAK) inhibitors, such as Ruxolitinib and Tofacitinib. Their favourable effects can not only be attributed to the blocking of IL-6, but also to the inhibition of other inflammatory messengers, which are also blocked by these kinases inhibitors. However, this therapeutic approach is also associated with an increased risk of infections.
Prof. Dr Stefan Rose-John
Kiel University
Institute of Biochemistry
Tel.: +49 (0)431 880 -3336
rosejohn@biochem.uni-kiel.de
Christoph Garbers, Sylvia Heink, Thomas Korn, Stefan Rose-John: Interleukin-6: designing specific therapeutics for a complex cytokine. Nature Reviews Drug Discovery. Published: 04 May 2018. doi:10.1038/nrd.2018.45
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