Details

Autor(en) / Beteiligte

• Lai, Fangfang
• Ji, Ming
• Huang, Lei
• Wang, Yunchen
• Xue, Nina
• Du, Tingting
• Dong, Kai
• Yao, Xiaoqing
• Jin, Jing
• Feng, Zhiqiang
• Chen, Xiaoguang

Titel

YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer

Ist Teil von

• Acta pharmaceutica Sinica. B, 2022-06, Vol.12 (6), p.2845-2858

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2022

Quelle

Elsevier ScienceDirect Journals Collection

Beschreibungen/Notizen

• 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. Orally administered prodrug IMMH-010 is transformed into YPD-29B, which can directly bind to PD-L1 protein and induce its dimerization and degradation, thus hindering the binding of PD-1/PD-L1. [Display omitted]