Department of Nuclear Medicine and Tracer Kinetics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Institute for Radiation Sciences, Osaka University, Suita, Japan.
Ann Nucl Med. 2021 Jun;35(6):702-718. doi: 10.1007/s12149-021-01612-9. Epub 2021 Apr 19.
Astatine (At) is a promising alpha emitter as an alternative to iodine (I). We are preparing the first-in-human (FIH) clinical trial of targeted alpha therapy for differentiated thyroid cancer in consultation with Pharmaceuticals and Medical Devices Agency. Here, we performed an extended single-dose toxicity examination under a reliability standard, as a preclinical safety assessment of [At]NaAt to determine the FIH dose.
[At]NaAt solution was injected into normal 6-week-old mice (male (n = 50) and female (n = 50), body weight: male 33.2 ± 1.7 g, female 27.3 ± 1.5 g), which were then divided into four groups: 5 MBq/kg (n = 20), 20 MBq/kg (n = 20), 50 MBq/kg (n = 30), saline control (n = 30). The mice were followed up for 5 days (primary evaluation point for acute toxicity: n = 80) or 14 days (n = 20: evaluation point for recovery) to monitor general condition and body weight change. At the end of the observation period, necropsy, blood test, organ weight measurement, and histopathological examination were performed. For body weight, blood test, and organ weight, statistical analyses were performed to compare data between the control and injected groups.
No abnormal findings were observed in the general condition of mice. In the 50 MBq/kg group, males (days 3 and 5) showed a significant decrease in body weight compared with the control. However, necropsy did not differ significantly beyond the range of spontaneous lesions. In the blood test, males (50 MBq/kg) and females (50 MBq/kg) showed a decrease in white blood cell and platelet counts on day 5, and recovery on day 14. In the testis, a considerable weight decrease was observed on day 14 (50 MBq/kg), and multinucleated giant cells were observed in all mice, indicating a significant change related to the administration of [At]NaAt.
In the extended single-dose toxicity study of [At]NaAt, administration of high doses resulted in weight loss, transient bone marrow suppression, and pathological changes in the testis, which require consideration in the FIH clinical trial.
砹（At）作为碘（I）的替代物，是一种很有前途的α发射体。我们正在与药品和医疗器械管理局协商，准备进行甲状腺癌靶向α治疗的首次人体（FIH）临床试验。在这里，我们根据可靠性标准进行了扩展的单次剂量毒性检查，作为[At]NaAt 的临床前安全性评估，以确定 FIH 剂量。
将[At]NaAt 溶液注入正常的 6 周龄小鼠（雄性（n=50）和雌性（n=50），体重：雄性 33.2±1.7g，雌性 27.3±1.5g），然后将它们分为四组：5MBq/kg（n=20）、20MBq/kg（n=20）、50MBq/kg（n=30）、生理盐水对照组（n=30）。对小鼠进行为期 5 天（急性毒性的主要评估点：n=80）或 14 天（n=20：恢复评估点）的随访，以监测一般情况和体重变化。在观察期结束时，进行尸检、血液检查、器官重量测量和组织病理学检查。对于体重、血液检查和器官重量，对对照组和注射组的数据进行了统计学分析。
未观察到小鼠一般状况异常。在 50MBq/kg 组中，雄性（第 3 天和第 5 天）与对照组相比，体重明显下降。然而，尸检未显示超出自发性病变范围的显著差异。在血液检查中，雄性（50MBq/kg）和雌性（50MBq/kg）在第 5 天白细胞和血小板计数下降，第 14 天恢复。在睾丸中，第 14 天（50MBq/kg）观察到明显的重量减轻，并且所有小鼠均观察到多核巨细胞，表明与[At]NaAt 给药相关的显著变化。
在[At]NaAt 的扩展单次剂量毒性研究中，高剂量给药导致体重减轻、短暂骨髓抑制和睾丸病理变化，这在 FIH 临床试验中需要考虑。
