Lai Fangfang, Ji Ming, Huang Lei, Wang Yunchen, Xue Nina, Du Tingting, Dong Kai, Yao Xiaoqing, Jin Jing, Feng Zhiqiang, Chen Xiaoguang
Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Tianjin Chase Sun Pharmaceutical Co., Ltd., Tianjin 300170, China.
Acta Pharm Sin B. 2022 Jun;12(6):2845-2858. doi: 10.1016/j.apsb.2022.02.031. Epub 2022 Mar 4.
PD-1 and PD-L1 antibodies have brought about extraordinary clinical benefits for cancer patients, and their indications are expanding incessantly. Currently, most PD-1/PD-L1 agents are administered intravenously, which may be uncomfortable for some cancer patients. Herein, we develop a novel oral-delivered small molecular, YPD-29B, which specifically targets human PD-L1. Our data suggested that YPD-29B could potently and selectively block the interaction between PD-L1 and PD-1, but did not inhibit any other immune checkpoints. Mechanistically, YPD-29B induced human PD-L1 dimerization and internalization, which subsequently activated T lymphocytes and therefore overcomes immunity tolerance . YDP-29B was modified as the YPD-30 prodrug to improve druggability. Using humanized mice with human PD-1 xenografts of human PD-L1 knock-in mouse MC38 cancer cells, we demonstrated that YPD-30 exhibited significant antitumor activity and was well tolerated . Taken together, our results indicate that YPD-30 serves as a promising therapeutic candidate for anti-human PD-L1 cancer immunotherapy.
程序性死亡受体 1（PD-1）和程序性死亡配体 1（PD-L1）抗体已为癌症患者带来了显著的临床益处，且其适应症在不断扩大。目前，大多数 PD-1/PD-L1 药物通过静脉给药，这对一些癌症患者来说可能会感到不适。在此，我们开发了一种新型口服小分子 YPD-29B，它特异性靶向人类 PD-L1。我们的数据表明，YPD-29B 能够有效且选择性地阻断 PD-L1 与 PD-1 之间的相互作用，但不抑制任何其他免疫检查点。从机制上讲，YPD-29B 诱导人类 PD-L1 二聚化和内化，随后激活 T 淋巴细胞，从而克服免疫耐受。YDP-29B 被修饰为 YPD-30 前药以提高成药性。利用携带人源化 PD-1 的人源化小鼠，其移植了人源 PD-L1 基因敲入的小鼠 MC38 癌细胞，我们证明 YPD-30 具有显著的抗肿瘤活性且耐受性良好。综上所述，我们的结果表明 YPD-30 是一种有前景的抗人 PD-L1 癌症免疫治疗候选药物。
