High-affinity Decoy Cytokines for IL-11 Receptor Super-agonism and Antagonism

Stanford researchers have developed a high-affinity IL-11 decoy cytokine for super-agonism and antagonism of the IL-11 receptor, enabling the treatment of a wide variety of diseases from inflammatory disease to cancer as well as research into IL-11 signaling pathways.

Interleukin-11 (IL-11) signaling plays a significant role in many diseases through its roles in inflammation, tissue repair, and cancer progression. For example, IL-11 blocking antibodies are in clinical development for pulmonary fibrosis while wild-type IL-11 is approved as a treatment for thrombocytopenia. However, stronger binders to the IL-11 receptor have the potential to be more effective treatments.

Stanford researchers therefore developed an IL-11 decoy cytokine with much higher affinity for the IL-11 receptor than the wild-type cytokine. High-throughput combinatorial screening identified mutations to IL-11 that increased its binding affinity to the IL-11 receptor 70-fold. Rresearchers identified additional mutations that converted this super-agonist to an antagonist by ablating binding to the gp130 co-receptor. Finally, they identified other mutations that enabled high-affinity binding to the mouse IL-11 receptor (~10-fold over wildtype) without affecting human IL-11 receptor binding. This engineered cytokine slows the growth of tumors in a mouse model of non-small cell lung cancer.

Stage of Development
In vivo: In mouse models of non-small cell lung cancer, treatment with the engineered cytokine slowed tumor growth in a dose-dependent manner