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<p>IL-21, as&#xa0;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,&#xa0;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.</p>

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An engineered IL-21 variant is a potent antitumor candidate for antitumor immunotherapy

  • 期刊论文

  • 发表日期：

    2025年10月17日

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  • Hui Wu,
  • Ya-ping Cheng,
  • Yu-long Liu,
  • Ruo-han Zhu,
  • Li-wen Ji,
  • Ming-kai Wang,
  • Quan-xiao Li,
  • Zhao-ling Shen,
  • Tian-lei Ying,
  • Yan-ling Wu

摘要

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.