68Ga定点标记纳米抗体检测非小细胞肺癌PD-L1表达及监测免疫治疗疗效的分子影像学研究

穿刺活检是目前检测程序性死亡受体-配体1(PD-L1)表达的唯一方法，但仅代表小区域PD-L1表达状态，无法反映整个肿瘤组织和转移病灶的情况，因此发展准确检测PD-L1表达的技术尤为重要。本课题组前期已建立制备高亲和力结合肿瘤PD-L1的纳米抗体的方法，筛选的纳米抗体可有效识别不同PD-L1表达水平的非小细胞肺癌(NSCLC)细胞，在体内具有良好的药代动力学性质和肿瘤摄取。在此基础上，本项目进一步开发68Ga定点标记的纳米抗体，制备新型检测PD-L1表达的PET分子探针；通过建立不同PD-L1表达水平和PD-L1阴性的免疫检查点人源化小鼠NSCLC模型，研究该分子探针在检测PD-L1表达的有效性，以及在免疫治疗NSCLC疗效监测中的价值。本项目探索一种体内检测PD-L1表达的PET显像技术，该技术以全面、准确、安全、可视化检测为目标，弥补现有PD-L1组织穿刺检验的缺陷。

Currently, Programmed Death Ligand 1 (PD-L1) immunohistochemistry (IHC) is the only method for evaluation of tumor PD-L1 expression. However, it can only be performed on tumors that are accessible for biopsy. It also provides limited information on the heterogeneity and dynamic nature of PD-L1 expression within the primary tumor itself and its metastases. Thus, it is very important to develop an alternative way to evaluate the PD-L1 expression. Recently, we have successfully generated and selected nanobodies that can bind to PD-L1 with high affinity and specificity. The selected nanobodies were able to differentiate NSCLC tumors with different PD-L1 expression levels, and display favorable pharmacokinetic properties and tumor uptake in vivo. Inspired by the preliminary data, we will develop novel 68Ga-labeled nanobodies as PET tracers for the visualization of tumor PD-L1 expression in this project. The 68Ga-labeled nanobodies will be used to determine the spatial expression of PD-L1 in the humanized mice before and during the course of PD-1 antibodies treatment. The aim of this project is to develop novel noninvasive nanobodies based PD-L1 PET/CT imaging technique for the efficacy assessment of PD-1 antibodies treatment in vivo. This comprehensive, precise, safe and visual technique can overcome the inherent deficiencies of current method in the detection of PD-L1 using tumor puncture biopsy.