目的为新型程序性死亡受体-1(PD-1)/程序性死亡配体-1(PD-L1)小分子抑制剂的研发提供参考。方法检索PubMed、Embase、Web of Science、ClinicalTrails.gov、中国知网、万方数据库2010年至2023年的PD-1/PD-L1小分子抑制剂相关文献,汇总并分析该类制剂的研发现状。结果与结论有成药潜力的PD-1/PD-L1小分子抑制剂共20种,包括CA-170(口服小分子抑制剂)、INCB086550(特异性PD-L1抑制剂)、DPPA-1(特异性抑制PD-1/PD-L1相互作用的多肽类拮抗剂)等,其中前两者已进入临床试验阶段。PD-1/PD-L1小分子抑制剂具有特异性抑制免疫检查点的药效作用特点,以及可口服、稳定性较好、膜通透性较高等优点,但其治疗效果仍需临床试验验证。
目的:利用两样本,多变量及双向孟德尔随机化(MR)研究设计,探究程序细胞死亡蛋白1 (programmeddeath-1, PD-1)及其配体(PD-1ligand, PD-L1)与心肌炎风险的因果关联。方法:从公开全基因组关联研究(GWAS)中提取PD-1/PD-L1与心肌炎的工具变量。采用逆方差加权法(IVW)作为主要的MR分析方法,辅以加权中位数(WM)、Robust adjusted profile score (RAPS)、MR-Egger、孟德尔随机化多效性残差和异常值(MR-PRESSO)、Cochran’s Q检验、留一法、水平多效性分析作为敏感性分析。结果:两样本MR的IVW结果提示,PD-L1与心肌炎具有负向因果关联[比值比(OR),0.619;95%置信区间(CI),0.434~0.884;P,0.008],敏感性分析结果表明因果关系稳健。在多变量MR中,PD-L1与心肌炎的负向因果关系依然存在(OR, 0.658;95% CI, 0.47~0.92, P, 0.015)。PD-1与心肌炎,心肌炎与PD-1/PD-L1的因果关联没有统计学意义。结论:该研究为PD-L1与心肌炎之间的负向因果关联提供了新的证据,而PD-1与心肌炎,心肌炎与PD-1/PD-L1没有直接因果关系。Objective: To investigate the causal association between programmed death-1 (PD-1) and its ligand (PD-1ligand, PD-L1) and the risk of myocarditis using a two-sample, multivariate and bidirectional Mendelian randomization (MR) study design. Methods: Instrumental variables for PD-1/PD-L1 and myocarditis were extracted from public genome-wide association studies (GWAS). Inverse variance weighting (IVW) was used as the main MR analysis method, supplemented by weighted median (WM), Robusta adjusted profile score (RAPS), MR-Egger, Mendelian randomization pleiotropic residuals and outliers (MR-PRESSO), Cochran’s Q test, leave-one-out method, and horizontal pleiotropy analysis as sensitivity analyses. Results: The IVW results of the two-sample MR suggested that PD-L1 had a negative causal association with myocarditis [odds ratio (OR), 0.619;95% confidence interval (CI), 0.434~0.884;P, 0.008], and the sensitivity analysis results showed th
