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An engineered IL-21 variant is a potent antitumor candidate for antitumor immunotherapy
Hui Wu1, Ya-Ping Cheng1, Yu-Long Liu1
1Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS) and Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
IL-21, as an immune agonist, has demonstrated limited therapeutic efficacy in cancer immunotherapy. To overcome this inherent limitation, we constructed a yeast surface-displayed IL-21 mutant library guided by the structure of the IL-21/IL-21 receptor (IL-21R). Following one round of magnetic bead sorting and three rounds of fluorescence-activated cell sorting, several variants were isolated and evaluated for receptor-binding affinity at the protein level. We identified an IL-21 Variant (IL-21V) featuring four critical mutations (Q19L, Y23N, V69T and K73Q) at the interaction interface with IL-21R. Compared with wild-type IL-21, IL-21V exhibited an approximately 7-fold increase in IL-21R binding affinity and a ~50-fold increase in STAT3 signalling pathway activation. In preclinical in vivo models, IL-21V exhibited broad-spectrum antitumor activity against B16F10 melanoma, MC38, and CT26 colorectal cancer. Notably, IL-21V exhibited significantly stronger antitumor effects compared to wild-type IL-21, even at a low dose of 0.15 mg/kg, highlighting its potential as a promising and effective immunotherapeutic candidate for cancer treatment.
IL-21, as an immune agonist, has demonstrated limited therapeutic efficacy in cancer immunotherapy. To overcome this inherent limitation, we constructed a yeast surface-displayed IL-21 mutant library guided by the structure of the IL-21/IL-21 receptor (IL-21R). Following one round of magnetic bead sorting and three rounds of fluorescence-activated cell sorting, several variants were isolated and evaluated for receptor-binding affinity at the protein level. We identified an IL-21 Variant (IL-21V) featuring four critical mutations (Q19L, Y23N, V69T and K73Q) at the interaction interface with IL-21R. Compared with wild-type IL-21, IL-21V exhibited an approximately 7-fold increase in IL-21R binding affinity and a ~50-fold increase in STAT3 signalling pathway activation. In preclinical in vivo models, IL-21V exhibited broad-spectrum antitumor activity against B16F10 melanoma, MC38, and CT26 colorectal cancer. Notably, IL-21V exhibited significantly stronger antitumor effects compared to wild-type IL-21, even at a low dose of 0.15 mg/kg, highlighting its potential as a promising and effective immunotherapeutic candidate for cancer treatment.
