An engineered interleukin-11 decoy cytokine inhibits receptor signaling and proliferation in lung adenocarcinoma

• Published in: Bioengineering & translational medicine Vol. 8; no. 6; pp. e10573 - n/a
• Main Authors: McIntosh, Brianna J, Hartmann, Griffin G, Yamada-Hunter, Sean A, Liu, Phillip, Williams, Camille F, Sage, Julien, Cochran, Jennifer R
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.11.2023; Wiley
• Subjects: Ablation; Affinity; Antibodies; Binding sites; Cancer; cancer progression; Cloning; Combinatorial analysis; Cytokines; Flow cytometry; IL‐11; Interleukins; Kinases; ligand/receptor interaction; Ligands; Mutation; protein engineering; Receptors; Yeast; IL‐11; protein engineering; cytokines; cancer progression; ligand/receptor interaction
• ISSN: 2380-6761; 2380-6761
• DOI: 10.1002/btm2.10573

The cytokine interleukin (IL)-11 has been shown to play a role in promoting fibrosis and cancer, including lung adenocarcinoma, garnering interest as an attractive target for therapeutic intervention. We used combinatorial methods to engineer an IL-11 variant that binds with higher affinity to the IL-11 receptor and stimulates enhanced receptor-mediated cell signaling. Introduction of two additional point mutations ablates IL-11 ligand/receptor association with the gp130 coreceptor signaling complex, resulting in a high-affinity receptor antagonist. Unlike wild-type IL-11, this engineered variant potently blocks IL-11-mediated cell signaling and slows tumor growth in a mouse model of lung cancer. Our approach highlights a strategy where native ligands can be engineered and exploited to create potent receptor antagonists.