エンジニアリングIL-21分泌におけるT細胞の薬物標的化可能なリガンド応答性安定化ドメインの使用

Dong Hyun Kim¹, Seo Jin Lee^1,2, Taeyoung Ahn¹

¹Laboratory of Cell & Gene Therapy, Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.

|December 27, 2025

Abstract:

Cytokine-based immunotherapies face challenges due to systemic toxicity and uncontrolled cytokine release. To enable precise control, we developed a druggable ligand-dependent IL-21 secretion system using destabilization domains (DDs). ER50 and DHFR facilitated ligand-responsive IL-21 secretion, with ER50 providing the most sustained regulation. Structural analysis revealed that N-terminal fusion improved IL-21 receptor binding, while C-terminal fusion weakened interactions. In primary T cells, IL-21 secretion promoted T stem-like (Tscm) cell differentiation, enhancing persistence for adoptive cell therapy. This system enables reversible, tunable cytokine control, offering a safer and more flexible approach for engineered T cell therapies.

キーワード:

不安定化ドメイン（DD）IL-21 免疫療法リガンド依存性調節 T細胞エンジニアリング

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