摘要：SummaryBlocking the activity of cytokines is an efficient strategy to combat inflammatory diseases. Interleukin-6 (IL-6) fulfills its pro-inflammatory properties via its soluble receptor (IL-6 trans-signaling). The selective trans-signaling inhibitor olamkicept (sgp130Fc) is currently in clinical development. We have previously shown that sgp130Fc can also efficiently block trans-signaling of the closely related cytokine IL-11, which elicits the question how selectivity for one of the two cytokines can be achieved. Using structural information, we show that the interfaces between IL-6R-gp130 and IL-11R-gp130, respectively, within the so-calledsite IIIare different between the two cytokines. Modification of an aromatic cluster around Q113 of gp130 within these interfaces allows the discrimination between IL-6 and IL-11 trans-signaling. Using recombinant sgp130Fc variants, we demonstrate that these differences can indeed be exploited to generate a truly selective IL-6 trans-signaling inhibitor. Our data highlight how the selectivity of a clinically relevant designer protein can be further improved.Graphical abstractDisplay OmittedHighlights•The designer protein olamkicept/sgp130Fc is an IL-6 trans-signaling inhibitor•Our data show that sgp130Fc also efficiently blocks IL-11 trans-signaling•The signaling complexes of IL-6 and IL-11 differ in the so-calledsiteIII•Mutation of Q113 of sgp130Fc allows selectivity between the cytokinesBiochemistry; Medical biochemistry; Immunology; Cell biology
