Extended single-dose toxicity study of 211AtNaAt in mice for the first-in-human clinical trial of targeted alpha therapy for differentiated thyroid cancer

• Published in: Annals of nuclear medicine 2021-06, Vol.35 (6), p.702
• Main Authors: Watabe, Tadashi, Kaneda-Nakashima, Kazuko, Ooe, Kazuhiro, Liu, Yuwei, Kurimoto, Kenta, Murai, Takashi, Shidahara, Yuka, Okuma, Kenji, Takeuchi, Masanori, Nishide, Masayuki, Toyoshima, Atsushi, Shinohara, Atsushi, Shirakami, Yoshifumi
• Format: Article
• Language: English
• ISSN: 1864-6433; 1864-6433
• DOI: 10.1007/s12149-021-01612-9

Astatine (211At) is a promising alpha emitter as an alternative to iodine (131I). 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 [211At]NaAt to determine the FIH dose.OBJECTIVEAstatine (211At) is a promising alpha emitter as an alternative to iodine (131I). 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 [211At]NaAt to determine the FIH dose.[211At]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.METHODS[211At]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