基于肿瘤PD1/PD-L1免疫检查点的新型小分子核素标记探针

目前PD-1/PD-L1免疫检查点通路抑制单抗药物在抗肿瘤治疗中取得突破性进展，为了更好地提升免疫治疗的效果、减少免疫副作用的发生，基于SPECT或PET的非侵入成像技术、对患者肿瘤PD-L1表达水平的全面实时监测成为临床开展肿瘤精准免疫治疗的迫切需求。本项目针对当前已报道的抗体类免疫显像探针普遍存在的瓶颈问题，另辟蹊径：设计“轻巧敏锐、结构明确”的小分子核素标记探针，并以其临床转化和应用为最终目标。项目拟采用小分子抑制剂BMS和(99m)Tc/(68)Ga-作为靶向活性基团和放射性标记核素，并在此基础上着重于关键问题---“标记偶联策略”的研究，构建[(99m)Tc(CO)3]-BMS及(68)Ga-DOTA/NOTA-BMS探针分子，开展相关生物性能评价和构效关系研究，研制开发精度不低于抗体，但分子量更小、药代动力学更理想的PD-L1靶向SPECT或PET显像剂。

Anticancer immunotherapies targeting the PD1/PD-L1 immune checkpoint have achieved spectacular success in the recent years. The noninvasive SPECT or PET imaging, which can provide rapid and real-time assessment of tumor PD-L1 expression and guide immunotherapeutic strategies to enhance the efficacy of immune modulation therapies, is urgently needed. Recently, although several radiolabeled antibodies targeting PD-L1 have been developed and on the leading edge of clinical translation. However, the great obstacles, such as the non-commercial long half-live radionuclides, long circulation times, slower blood clearance, high radiation dose and undesirable immunological side effects have limited the clinical application of radiolabeled protein-based radiotracers. Therefore, we focus on the low molecular weight, small-molecule based probes, which are desirable candidates for clinical application due to their fast clearance and synthetic tractability. In this study, the novel 99mTc/68Ga-labeled small-molecule probes are constructed on the basis of BMS small-molecule inhibitors of PD-1/PDL1 interaction. Focusing on the key issue of metallic radionuclides labeled molecular probes, “whole-body design strategy” and “coupling strategy” are used to build the [(99m)Tc(CO)3]-BMS molecules and [(68)Ga-DOTA/NOTA]-BMS conjugations, respectively. In vitro and in vivo biological evaluation of these radiolabeled BMS-derivatives will be carried out. Structure-activity relationship will be studied, to develop the small-molecule SPECT or PET probes with high PD-L1 affinity and optimized pharmacokinetics.