A synthetic human antibody antagonizes IL-18Rβ signaling through an allosteric mechanism

Publication date: Available online 15 January 2020Source: Journal of Molecular BiologyAuthor(s): Shusu Liu, Shane Miersch, Ping Li, Bingxin Bai, Chunchun Liu, Wenming Qin, Jie Su, Haiming Huang, James Pan, Sachdev S. Sidhu, Donghui WuAbstractThe interleukin-18 subfamily belongs to the interleukin-1 family and plays important roles 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 abstractBinding 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 ...
Source: Journal of Molecular Biology - Category: Molecular Biology Source Type: research