Lv Gaochao, Hu Xin, Zhang Nan, Zhu Junyi, Gao Xiaoqing, Xi Hongjie, Peng Ying, Xie Quan, Qiu Ling, Lin Jianguo
NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China; Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China.
Bioorg Chem. 2024 Dec;153:107810. doi: 10.1016/j.bioorg.2024.107810. Epub 2024 Sep 7.
Although antibody-based immune checkpoint blockades have been successfully used in antitumor immunotherapy, the low response rate is currently the main problem. In this work, a small-molecule programmed cell death-ligand (PD-L1) inhibitor, LG-12, was developed and radiolabeled with I to obtain the chemically and biologically identical radiopharmaceutical [I]LG-12, which aimed to improve the antitumor effect by combination of LG-12 and [I]LG-12. LG-12 showed high inhibitory activity to PD-1/PD-L1 interaction. The results of cell uptake and biodistribution studies indicated that [I]LG-12 could specifically bind to PD-L1 in B16-F10 tumors. It could induce immunogenic cell death and the release of high mobility group box 1 and calreticulin. The combination of [I]LG-12 and LG-12 could significantly inhibit tumor growth and resulted in enhanced antitumor immune response. This PD-L1 small-molecule inhibitor based combination strategy has great potential for tumor treatment.
尽管基于抗体的免疫检查点阻断疗法已成功应用于抗肿瘤免疫治疗，但目前低响应率仍是主要问题。在本研究中，开发了一种小分子程序性细胞死亡配体（PD-L1）抑制剂LG-12，并用碘进行放射性标记，得到化学和生物学性质相同的放射性药物[I]LG-12，旨在通过LG-12与[I]LG-12联合使用来提高抗肿瘤效果。LG-12对PD-1/PD-L1相互作用表现出高抑制活性。细胞摄取和生物分布研究结果表明，[I]LG-12可特异性结合B16-F10肿瘤中的PD-L1。它可诱导免疫原性细胞死亡以及高迁移率族蛋白B1和钙网蛋白的释放。[I]LG-12与LG-12联合使用可显著抑制肿瘤生长，并增强抗肿瘤免疫反应。这种基于PD-L1小分子抑制剂的联合策略在肿瘤治疗方面具有巨大潜力。
