@article {Watabe1216, author = {Tadashi Watabe and Kazuko Kaneda-Nakashima and Kazuhiro Ooe and Yuwei Liu and Kenta Kurimoto and Atsushi Toyoshima and Atsushi Shinohara and Yoshifumi Shirakami}, title = {Extended single-dose toxicity study of [211At]NaAt in mice for the FIH clinical trial of targeted alpha therapy for differentiated thyroid cancer}, volume = {62}, number = {supplement 1}, pages = {1216--1216}, year = {2021}, publisher = {Society of Nuclear Medicine}, abstract = {1216Purpose: We recently reported anti-tumor effect of astatine ([211At]NaAt) in the preclinical study using xenograft model. We are now preparing for the first-in-human (FIH) clinical trial of targeted alpha therapy for differentiated thyroid cancer along with PMDA (Japanese authority for drug approval) consultation. In this study, we performed an extended single-dose toxicity examination under reliability standard as a preclinical safety assessment of [211At]NaAt to decide FIH dose. Methods: [211At]NaAt solution was injected into the normal ICR mice (5-6 weeks old, male (n = 50) and female (n = 50), body weight: 30.2 {\textpm} 3.3g). Mice were divided into four groups: 5 MBq/kg (n=20), 20 MBq/kg (n=20), 50 MBq/kg (n=30), and saline control (n = 30). Mice were followed up for 5 days (main 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, autopsy, blood test, organ weight measurement, and histopathological examination were performed. For body weight, blood test, and organ weight, statistical analyses were performed between the control group and the injected group by Dunnett{\textquoteright}s test. Results: No abnormal finding was observed in the monitoring of general condition. In 50 MBq/kg group, male (day3 and day5) and female (day5) showed significant decrease in body weight compared to control. In autopsy, there is no significant change beyond the range of spontaneous lesions. In the blood test, male (50 MBq/kg) and female (50 MBq/kg) showed decrease in white blood cell and platelet counts at day5 and recovery at day14, suggesting transient bone marrow suppression. In 50MBq/kg group, significant increase was observed in total protein, albumin, and total cholesterol, possibly due to hypothyroidism. No renal toxicity was observed in the blood test. Spleen showed weight decrease in 50MBq/kg group (male and female) and 20 MBq/kg group (female) at day5. Salivary gland also showed weight decrease in 50MBq/kg group (male: day14 and female: day5). However, these organs showed no significant change in the histology. In testis, there was a marked weight decrease at day14 (50 MBq/kg), and multinucleated giant cells were observed in all mice, indicating the significant change related to administration of [211At]NaAt. In thyroid, colloidal decrease, degeneration and necrosis of follicular epithelial cells and infiltration of inflammatory cells were observed with increasing dose, suggesting well-known ablation effect. There was no significant change in other major organs in histology. Conclusions: In the extended single-dose toxicity study of [211At]NaAt conducted under the reliability standard, no abnormal findings exceeding the expectations of previous study (Liu Y, et al. Transl Oncol. 2020) were observed. At high doses of [211At]NaAt (50MBq / kg), weight loss, transient bone marrow suppression, and pathological changes in the testis were observed, which require caution in the FIH clinical trial.}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/62/supplement_1/1216}, eprint = {https://jnm.snmjournals.org/content}, journal = {Journal of Nuclear Medicine} }