An IL-21-derived neokine with enhanced anti-tumor efficacy 2594

Abstract Description IL-21 is a pleiotropic common-gamma-chain cytokine with diverse actions on immune cells. IL-21 promotes cytotoxicity of CD8+ T cells and NK cells and has been evaluated as a cancer therapy in phase I and II clinical trials. Although the pre-clinical trials of IL-21-based cancer immunotherapy have been encouraging, the precise effect of IL-21 on anti-tumor responses remains incompletely understood. Despite its promise, IL-21 has lower stability resulting in suboptimal pharmacokinetic properties and the limited efficacy of human IL-21 in mouse has complicated the use of animal models to predict the toxicity and activity of IL-21 therapeutics in human. To overcome these limitations, we designed a de novo protein mimic of IL-21 named “21h10” using Rosetta helical sampling and loop-building methodology. 21h10 showed higher stability and activity in both mouse and human. 21h10 strongly induced pSTAT1 and pSTAT3 signaling in CD8+ and CD4+ T cells. 21h10 showed potent anti-tumor efficacy in melanoma and orthotopic pancreatic cancer mouse models as compared to native IL-21. In the tumor microenvironment, 21h10 increased IFNg and granzyme B production in cytotoxic CD8+ T cells. Moreover, 21h10 promoted Th1 cells while suppressing the development and expansion of Tregs. Thus, 21h10 is a promising IL-21-derived neokine with robust anti-tumor efficacy and translational potential for targeting tumors that are unresponsive to checkpoint blockade and current cytokine-based immunotherapies. Topic Categories Cytokines and Chemokines and Their Receptors (CCR)