Awadasseid Annoor, Wang Rui, Zhang Koutian, Zhou Shijia, Zhang Feng, Jin Zeyun, Zhang Wen
Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Deqing 313299, China; Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Deqing 313299, China; Zhejiang Qingzhenghong Technology Co, Ltd, Hangzhou 311121, China.
Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Deqing 313299, China; Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Deqing 313299, China.
Bioorg Med Chem. 2025 Oct 1;128:118268. doi: 10.1016/j.bmc.2025.118268. Epub 2025 Jun 3.
The PD-1/PD-L1 immune checkpoint plays a crucial role in tumor immune evasion, making it a prime target for cancer immunotherapy. While small-molecule inhibitors have emerged as promising alternatives to monoclonal antibodies, differences in PD-L1 exposure between human and murine models present challenges in preclinical evaluation. In this study, we investigate the cross-species druggability of two potent small-molecule inhibitors, A56 and HD10, by comparing their binding affinity, immune modulation, and anti-tumor efficacy in both human and mouse PD-L1 models. For the first time, we demonstrated that murine PD-1 and human PD-L1 form effective immune checkpoints and function in vivo. Our findings highlight the importance of species-specific evaluations in immune checkpoint inhibitor development and the careful selection of appropriate animal models. Flow cytometry and in vivo analyses reveal that A56 and HD10 enhance CD8 T cell infiltration and anti-tumor activity in both species, with notable variations in immune responses between human and murine PD-L1 contexts. The dual-targeting capability of A56 and HD10 supports their potential as cost-effective, orally available immunotherapies, warranting further clinical investigation.
PD-1/PD-L1免疫检查点在肿瘤免疫逃逸中起着关键作用，使其成为癌症免疫治疗的主要靶点。虽然小分子抑制剂已成为单克隆抗体的有前景的替代物，但人类和小鼠模型之间PD-L1暴露的差异在临床前评估中带来了挑战。在本研究中，我们通过比较两种强效小分子抑制剂A56和HD10在人和小鼠PD-L1模型中的结合亲和力、免疫调节和抗肿瘤功效，研究了它们的跨物种成药潜力。我们首次证明，小鼠PD-1和人类PD-L1形成有效的免疫检查点并在体内发挥作用。我们的研究结果突出了在免疫检查点抑制剂开发中进行物种特异性评估以及谨慎选择合适动物模型的重要性。流式细胞术和体内分析表明，A56和HD10在两种物种中均增强了CD8 T细胞浸润和抗肿瘤活性，在人和小鼠PD-L1背景下的免疫反应存在显著差异。A56和HD10的双靶点能力支持它们作为经济高效、口服可用的免疫疗法的潜力，值得进一步的临床研究。
