Hitting a complex target: an update on interleukin-6 trans-signalling

Introduction:Interleukin-6 (IL-6) is a key target in inflammation and cancer. Selective inhibition of IL-6 trans-signalling could provide the same or even higher therapeutic efficacy with a better side effect profile than complete IL-6 inhibition. Animal studies with IL-6 inhibitors show that the classic IL-6 signalling pathway via the membrane-bound IL-6 receptor (IL-6R) has important physiological functions, whereas blocking the trans-signalling pathway via the soluble IL-6R (sIL-6R) is sufficient to prevent or treat IL-6-driven diseases. Due to the success of the anti-IL-6R antibody tocilizumab and difficulties of constructing selective trans-signalling inhibitors, most drug candidates in clinical development target IL-6 or IL-6R and, thus, both IL-6 pathways. By contrast, the fusion protein sgp130Fc selectively targets IL-6/sIL-6R trans-signalling by utilising the soluble gp130 receptor as the natural inhibitor of trans-signalling.Areas covered:The authors summarise recent developments in the field with a focus on animal studies highlighting the mechanistic differences between classic and trans-signalling and their therapeutic implications.Expert opinion:Characterising disease mechanisms in terms of the employed IL-6 pathways will help to select the right therapeutic IL-6 inhibitor in the future. The trans-signalling inhibitor sgp130Fc is about to enter the clinic and holds promise for a clinically different profile in comparison with complete IL-6 inhibitors.