Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Cell Rep Med. 2024 May 21;5(5):101531. doi: 10.1016/j.xcrm.2024.101531. Epub 2024 May 1.
The clinical applications of immunocytokines are severely restricted by dose-limiting toxicities. To address this challenge, here we propose a next-generation immunocytokine concept involving the design of LH05, a tumor-conditional anti-PD-L1/interleukin-15 (IL-15) prodrug. LH05 innovatively masks IL-15 with steric hindrance, mitigating the "cytokine sink" effect of IL-15 and reducing systemic toxicities associated with wild-type anti-PD-L1/IL-15. Moreover, upon specific proteolytic cleavage within the tumor microenvironment, LH05 releases an active IL-15 superagonist, exerting potent antitumor effects. Mechanistically, the antitumor efficacy of LH05 depends on the increased infiltration of CD8 T and natural killer cells by stimulating the chemokines CXCL9 and CXCL10, thereby converting cold tumors into hot tumors. Additionally, the tumor-conditional anti-PD-L1/IL-15 can synergize with an oncolytic virus or checkpoint blockade in advanced and metastatic tumor models. Our findings provide a compelling proof of concept for the development of next-generation immunocytokines, contributing significantly to current knowledge and strategies of immunotherapy.
免疫细胞因子的临床应用受到剂量限制毒性的严重限制。为了解决这一挑战，我们在这里提出了一种涉及 LH05 设计的下一代免疫细胞因子概念，LH05 是一种肿瘤条件性抗 PD-L1/白细胞介素 15（IL-15）前药。LH05 创新性地用空间位阻掩盖 IL-15，减轻了 IL-15 的“细胞因子陷阱”效应，并降低了与野生型抗 PD-L1/IL-15 相关的全身毒性。此外，在肿瘤微环境中特异性蛋白水解切割后，LH05 释放出一种活性的 IL-15 超激动剂，发挥强大的抗肿瘤作用。从机制上讲，LH05 的抗肿瘤疗效取决于通过刺激趋化因子 CXCL9 和 CXCL10 增加 CD8 T 细胞和自然杀伤细胞的浸润，从而将冷肿瘤转化为热肿瘤。此外，肿瘤条件性抗 PD-L1/IL-15 可与溶瘤病毒或检查点阻断在晚期和转移性肿瘤模型中协同作用。我们的研究结果为开发下一代免疫细胞因子提供了令人信服的概念验证，为当前的免疫治疗知识和策略做出了重要贡献。
