Selective rather than blanket: How the treatment of interleukin-6-driven diseases can be refined

Press Release of the Cluster of Excellence “Precision Medicine in Chronic Inflammation” (PMI)

25 September 2026

Selective rather than blanket: How the treatment of interleukin-6-driven diseases can be refined

Interleukin-6 (IL-6) is a contradictory molecule in immunology. It helps the liver regenerate after injury and protects against infections, yet it also drives chronic inflammation in rheumatic diseases, inflammatory bowel disease and atherosclerosis. Current drugs block IL-6 across the board and cannot separate these two sides: they protect against inflammation but also switch off its beneficial functions. The team of Professor Stefan Rose-John (Institute of Biochemistry, Kiel University), Dr Georg Wätzig (CONARIS Research Institute AG, Kiel) and Professor Stefan Schreiber (Department of Internal Medicine I, University Hospital Schleswig-Holstein, and Cluster of Excellence Precision Medicine in Chronic Inflammation) now shows why this can change. Their new review article appears in Nature Reviews Drug Discovery, the world's leading journal for drug development.

Two pathways, one effect

Conventional drugs cannot separate these two sides because of the way IL-6 works: The messenger can reach cells via two different routes. In the first, "classic" signalling, IL-6 binds to a receptor carried by only a few cell types, such as liver cells and certain immune cells. The complex of IL-6 and its receptor is then bound by a second receptor, the co-receptor glycoprotein 130 (gp130), which transmits the signal into the cell. This pathway is predominantly protective: it supports tissue regeneration and the defence against infections.

In the second route, known as trans-signalling, the IL-6 receptor must be present in soluble form in the blood. This soluble IL-6 receptor is produced mainly by proteolysis. It can bind IL-6 and, together with it, reach any cell in the body, because all cells carry the co-receptor gp130. This is the pathway that drives disease in chronic inflammatory conditions such as rheumatoid arthritis or inflammatory bowel disease. The problem is that the antibody therapies available today do not distinguish between the two pathways. These include tocilizumab and sarilumab, which are directed against the IL-6 receptor, and they automatically block both routes.

"For a long time, IL-6 was regarded primarily as a driver of inflammation," says Professor Stefan Rose-John. "Only with our discovery that the messenger acts via two distinct pathways did it become clear that its protective and harmful effects should, in principle, be separable."

The price of imprecision

This lack of distinction comes at a price. Antibodies of this drug class have fundamentally improved the treatment of rheumatoid arthritis and other autoimmune diseases. However, because they also block protective classic signalling, clinical studies repeatedly report increased susceptibility to infections and altered blood lipid levels. In rarer cases they report more serious, sometimes life-threatening complications.

Animal studies show a clear pattern. When only trans-signalling is blocked, the protective effect of IL-6 is preserved. The disease usually improves just as much as under complete IL-6 blockade, and in some cases even more. In a sepsis model, for example, inhibiting trans-signalling within a certain dose range saved all mice from death by severe sepsis. Complete blockade, by contrast, offered no advantage over the placebo.

Selective rather than blanket

This is exactly where the approach described in the review comes in: blocking trans-signalling alone. The most advanced drug of this kind is olamkicept, the result of years of development work by the team. It selectively captures the soluble receptor complex responsible for disease-causing signalling and leaves protective signalling untouched. "It is not enough simply to block IL-6 less strongly," says Dr Georg Wätzig. "The key was to find a molecular target at which only the disease-causing pathway can be interrupted, without impairing protective signalling."

In a randomised clinical trial in patients with ulcerative colitis, 58.6 per cent responded to olamkicept therapy, compared with 34.5 per cent on placebo. The side effects known from other IL-6 therapies did not occur.

What comes next

Development is continuing: together with an international partner, olamkicept is to be taken into the decisive Phase III of clinical testing. The authors also see this as a model for the future of inflammation medicine. The principle of switching off only the disease-causing pathway of a messenger while preserving the protective one could, in principle, be transferred to other messengers as well. In the long term, this could mean more effective therapies with fewer side effects for chronic inflammatory diseases, because they act precisely where a disease actually arises.

Original publication

Rose-John, S., Waetzig, G. H. & Schreiber, S. Refining therapeutic targeting of interleukin-6 by signalling mode selectivity. Nature Reviews Drug Discovery (2026). DOI: https://doi.org/10.1038/s41573-026-01536-x