68Ga定点标记ICAM-1纳米抗体诊断碘难治性甲状腺癌及监测光免疫治疗疗效的分子影像学研究

碘难治性甲状腺癌主要包括碘难治性分化型甲状腺癌和未分化型甲状腺癌，分化程度差，是造成甲状腺癌所致死亡的最主要原因。探索碘难治性甲状腺癌肿瘤标志物、研发标志物特异性分子影像探针是优化碘难治性甲状腺癌临床诊疗的有力措施。本课题前期研究表明ICAM-1是碘难治性甲状腺癌的标志物，发现基于64Cu标记单克隆抗体探针的免疫PET显像可精准诊断皮下及原位碘难治性甲状腺癌。相比单克隆抗体探针，纳米抗体探针显像靶本比更高、且更易临床转化。因此，本课题拟通过68Ga标记纳米抗体制备ICAM-1特异性免疫PET显像探针，比较随机标记与定点标记探针诊断性能差异；并进一步构建基于纳米抗体ICAM-1特异性光免疫治疗探针IR700-ICAM-1，研究光免疫治疗抑制原位碘难治性甲状腺癌的效能。本课题将创新纳米抗体定点标记方法，构建基于纳米抗体ICAM-1特异性分子影像诊疗体系，优化碘难治性甲状腺癌诊疗，临床意义显著。

Radioiodine-refractory thyroid cancers mainly include radioiodine-refractory differentiated thyroid cancer (RR-DTC) and anaplastic thyroid cancer (ATC), which are virtually less differentiated or undifferentiated, respectively. Radioiodine-refractory thyroid cancer is the main cause of thyroid cancer-related deaths. In this setting, exploiting tumor makers highly specific for radioiodine-refractory thyroid cancers and developing marker-targeted molecular imaging probes will hopefully optimize the management of radioiodine-refractory thyroid cancers. Previously, we have validated that ICAM-1 is a promising tumor marker for radioiodine-refractory thyroid cancers. More importantly, we found that ICAM-1–targeted immunoPET imaging with a 64Cu-labeled monoclonal antibody (mAb) efficiently delineated both subcutaneous and orthotopic radioiodine-refractory thyroid cancers. When compared to radiotracers derived from mAbs, these based on Nanobodies permit same-day imaging with higher target-to-background ratios. Besides, it is easier to translate radiotracers based on Nanobodies for clinical use. Herein, this study aims to develop ICAM-1–targeted immunoPET imaging probes via labeling ICAM-1–targeted Nanobodies with 68Ga. Both nonspecific and microbial transglutaminase (MTGase)-mediated site-specific radiolabeling will be used and compared in the current study. Moreover, photoimmunotherapy agents (IR700-ICAM-1) will be conjugated using the ICAM-1–targeted Nanobodies and their therapeutic efficacies will be explored in orthotopic ATC models. This study will establish protocols for site-specific radiolabeling of Nanobodies with MTGase and develop ICAM-1–targeted theranostic probes, which will hopefully optimize the clinical management of radioiodine-refractory thyroid cancers.