Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
Hangzhou Institute of Medicine Chinese Academy of Sciences, Hangzhou 310018 Zhejiang, China.
Sci Adv. 2024 Aug 23;10(34):eadp8647. doi: 10.1126/sciadv.adp8647.
Agonistic antibodies against CD137 have been demonstrated to completely regress established tumors through activating T cell immunity. Unfortunately, current CD137 antibodies failed to benefit patients with cancer. Moreover, their antitumor mechanisms in vivo remain to be determined. Here, we report the development of a small molecular CD137 agonist, JNU-0921. JNU-0921 effectively activates both human and mouse CD137 through direct binding their extracellular domains to induce oligomerization and signaling and effectively shrinks tumors in vivo. Mechanistically, JNU-0921 enhances effector and memory function of cytotoxic CD8 T cells (CTLs) and alleviates their exhaustion. JNU-0921 also skews polarization of helper T cells toward T helper 1 type and enhances their activity to boost CTL function. Meanwhile, JNU-0921 attenuates the inhibitory function of regulatory T cells on CTLs. Our current work shows that JNU-0921 shrinks tumors by enhancing the cytotoxicity of CTLs in cis and in trans and sheds light on strategy for developing CD137 small molecular agonists.
激动型抗 CD137 抗体已被证明可通过激活 T 细胞免疫来完全消退已建立的肿瘤。不幸的是，目前的 CD137 抗体未能使癌症患者受益。此外，其体内抗肿瘤机制仍有待确定。在这里，我们报告了一种小分子 CD137 激动剂 JNU-0921 的开发。JNU-0921 通过直接结合其细胞外结构域激活人和小鼠 CD137，有效诱导寡聚化和信号转导，并在体内有效缩小肿瘤。在机制上，JNU-0921 增强了细胞毒性 CD8 T 细胞（CTL）的效应器和记忆功能，并减轻了它们的衰竭。JNU-0921 还使辅助性 T 细胞向 T 辅助 1 型极化，并增强其活性以增强 CTL 功能。同时，JNU-0921 减弱了调节性 T 细胞对 CTL 的抑制功能。我们目前的工作表明，JNU-0921 通过增强 CTL 的细胞毒性来缩小肿瘤，这为开发 CD137 小分子激动剂提供了策略。
