Zhou Huimin, Bao Guangfa, Wang Ziqiang, Zhang Buchuan, Li Dan, Chen Lixing, Deng Xiaoyun, Yu Bo, Zhao Jun, Zhu Xiaohua
Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China.
Department of Anatomy, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
EJNMMI Res. 2022 Jun 13;12(1):35. doi: 10.1186/s13550-022-00906-x.
Adnectin is a protein family derived from the 10th type III domain of human fibronectin (Fn3) with high-affinity targeting capabilities. Positron emission tomography (PET) probes derived from anti-programmed death ligand-1 (PD-L1) Adnectins, including F- and Ga-labeled BMS-986192, are recently developed for the prediction of patient response to immune checkpoint blockade. The Ga-labeled BMS-986192, in particular, is an attractive probe for under-developed regions due to the broader availability of Ga. However, the pharmacokinetics and biocompatibility of Ga-labeled BMS-986192 are still unknown, especially in non-human primates, impeding its further clinical translation.
We developed a variant of Ga-labeled BMS-986192 using 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) as the radionuclide-chelator. The resultant probe, Ga-NODAGA-BMS986192, was evaluated in terms of targeting specificity using a bilateral mouse tumor model inoculated with wild-type B16F10 and B16F10 transduced with human PD-L1 (hPD-L1-B16F10). The dynamic biodistribution and radiation dosimetry of this probe were also investigated in non-human primate cynomolgus.
Ga-NODAGA-BMS986192 was prepared with a radiochemical purity above 99%. PET imaging with Ga-NODAGA-BMS986192 efficiently delineated the hPD-L1-B16F10 tumor at 1 h post-injection. The PD-L1-targeting capability of this probe was further confirmed using in vivo blocking assay and ex vivo biodistribution studies. PET dynamic imaging in both mouse and cynomolgus models revealed a rapid clearance of the probe via the renal route, which corresponded to the low background signals of the PET images. The probe also exhibited a favorable radiation dosimetry profile with a total-body effective dose of 6.34E-03 mSv/MBq in male cynomolgus.
Ga-NODAGA-BMS986192 was a feasible and safe tool for the visualization of human PD-L1. Our study also provided valuable information on the potential of targeted PET imaging using Adnectin-based probes.
黏附素是一种源自人纤连蛋白第10个III型结构域（Fn3）的蛋白质家族，具有高亲和力靶向能力。最近开发了源自抗程序性死亡配体-1（PD-L1）黏附素的正电子发射断层扫描（PET）探针，包括F和Ga标记的BMS-986192，用于预测患者对免疫检查点阻断的反应。特别是Ga标记的BMS-986192，由于Ga的可用性更广泛，对于欠发达地区是一种有吸引力的探针。然而，Ga标记的BMS-986192的药代动力学和生物相容性仍然未知，尤其是在非人类灵长类动物中，这阻碍了其进一步的临床转化。
我们使用1,4,7-三氮杂环壬烷-1-戊二酸-4,7-乙酸（NODAGA）作为放射性核素螯合剂开发了一种Ga标记的BMS-986192变体。使用接种野生型B16F10和转导人PD-L1（hPD-L1-B16F10）的双侧小鼠肿瘤模型，对所得探针Ga-NODAGA-BMS986192的靶向特异性进行了评估。还在食蟹猴非人类灵长类动物中研究了该探针的动态生物分布和辐射剂量学。
制备的Ga-NODAGA-BMS986192放射化学纯度高于99%。注射后1小时，用Ga-NODAGA-BMS986192进行的PET成像有效地勾勒出hPD-L1-B16F10肿瘤。使用体内阻断试验和体外生物分布研究进一步证实了该探针的PD-L1靶向能力。在小鼠和食蟹猴模型中的PET动态成像显示，该探针通过肾脏途径快速清除，这与PET图像的低背景信号相对应。该探针还表现出良好的辐射剂量学特征，雄性食蟹猴的全身有效剂量为6.34E-03 mSv/MBq。
Ga-NODAGA-BMS986192是用于可视化人PD-L1的可行且安全的工具。我们的研究还提供了关于使用基于黏附素的探针进行靶向PET成像潜力的有价值信息。
