A Synthetic Human Antibody Antagonizes IL-18Rβ Signaling Through an Allosteric Mechanism. Issue 4 (14th February 2020) - Liu, Shusu
Abstract: The interleukin-18 subfamily belongs to the interleukin-1 family and plays an important role in modulating innate and adaptive immune responses. Dysregulation of IL-18 has been implicated in or correlated with numerous diseases, including inflammatory diseases, autoimmune disorders, and cancer. Thus, blockade of IL-18 signaling may offer therapeutic benefits in many pathological settings. Here, we report the development of synthetic human antibodies that target human IL-18Rβ and block IL-18-mediated IFN-γ secretion by inhibiting NF-κB and MAPK dependent pathways. The crystal structure of a potent antagonist antibody in complex with IL-18Rβ revealed inhibition through an unexpected allosteric mechanism. Our findings offer a novel means for therapeutic intervention in the IL-18 pathway and may provide a new strategy for targeting cytokine receptors. Graphical abstract: Binding of scFv 3131 to IL-18Rβ blocks formation of the IL-18/IL-18Rα/IL-18Rβ ternary complex. Superposition of IL-18Rβ in complex with scFv 3131 (PDB code: 6KN9 ) on to the ternary complex (PDB code: 3WO4 ) was performed using the D3 domains of the two IL-18Rβ molecules as reference. In the IL-18Rβ/scFv 3131 complex, IL-18Rβ is colored in magenta, and scFv 3131 is colored in dark grey (VH) and light grey (VL). In the IL-18/IL-18Rα/IL-18Rβ ternary complex, IL-18Rβ is colored in wheat, IL-18Rα is colored in cyan, and IL-18 is colored in yellow. The D1-D2 domains of IL-18Rβ undergo a 104° rotation relative to the D3 domain in the two structures. Image 1 Highlights: IL-18/IL-18Rα/IL-18Rβ ternary complex is essential for downstream IFNγ secretion. Antibodies to human IL-18Rβ were identified from a phage-displayed antibody library. One antibody was identified as a potent antagonist to inhibit IFNγ secretion. Crystal structure shows the antibody can disturb the formation of the ternary complex. The antibody has the potential to treat diseases caused by excessive IL-18 activation.