Autor: |
Fangfang Lai, Ming Ji, Lei Huang, Yunchen Wang, Nina Xue, Tingting Du, Kai Dong, Xiaoqing Yao, Jing Jin, Zhiqiang Feng, Xiaoguang Chen |
Jazyk: |
angličtina |
Rok vydání: |
2022 |
Předmět: |
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Zdroj: |
Acta Pharmaceutica Sinica B, Vol 12, Iss 6, Pp 2845-2858 (2022) |
Druh dokumentu: |
article |
ISSN: |
2211-3835 |
DOI: |
10.1016/j.apsb.2022.02.031 |
Popis: |
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 in vitro. 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 in vivo. Taken together, our results indicate that YPD-30 serves as a promising therapeutic candidate for anti-human PD-L1 cancer immunotherapy. |
Databáze: |
Directory of Open Access Journals |
Externí odkaz: |
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