Evaluation of acute radiotoxicity profile of alpha-particle-emitting meta-²¹¹At-astato-benzylguanidine (²¹¹At-MABG) in normal BALB/c mice

Objectives: Given the limited treatment approaches currently available for patients with metastatic pheochromocytoma and paraganglioma (PPGL), new effective approaches are being sought. Treatment using ¹³¹I-meta-iodobenzylguanidine (¹³¹I-MIBG) has limited survival benefits for patients with metastatic PPGL, but it is currently considered one of the standard therapeutic approaches. In theory, the alpha-particle-emitting radiopharmaceutical meta-²¹¹At-astato-benzylguanidine (²¹¹At-MABG) could be a very effective targeted treatment for metastatic PPGL with limited side effects. Our preliminary study showed that ²¹¹At-MABG had a tumor-reducing effect similar to that associated with ¹³¹I-MIBG, which is considered one of the current treatment options (Zhao S, et al. SNMMI 2020, Pub #1316). Sudo et al. reported the results of their preclinical toxicity study of ²¹¹At-MABG in normal ICR mice (Transl Oncol, 2019;12:879). The purpose of this study was to further evaluate the acute radiotoxicity of ²¹¹At-MABG in normal mice under the extended single-dose toxicity format to obtain information required before the first-in-human phase 1 trial.

Methods: BALB/c mouse were selected as test species because they are known to be susceptible to radiation. Normal male mice (9 weeks old) were randomly assigned to five groups and intravenously injected with a single dose of 3.7, 1.11, 0.37, or 0.11 MBq of ²¹¹At-MABG (n=10-15, each group) or a vehicle solvent (n=9). Until the 15th day after the injection, the general condition score and body weight were measured every day. From the 16th day after the injection, the general condition score and body weight were measured three times per week. Three or five mice in each group were dissected, and necropsy, histopathology, organ weight measurement, hematology and blood chemistry tests were performed 5, 14, and 28 days after the injection.

Results: No general changes were observed in any mouse immediately after injection as well as on day 0. The mice in the group injected with 3.7 MBq of ²¹¹At-MABG gradually showed a decline in their activity from day 1 to day 5, and all mice died on day 6 or 7 showing symptoms of diarrhea. Necropsy the mice on day 5 revealed that extensive damage in the small and large intestines. All mice in the groups injected with 0.11, 0.37, or 1.11 MBq of ²¹¹At-MABG survived until day 14 or 28. There were no significant changes in the general condition score (p=NS) or body weight among the mice injected with 0.11-1.11 MBq of ²¹¹At-MABG (p=NS) despite the transient body weight loss observed in the mice injected with 1.11 MBq of ²¹¹At-MABG on day 5 (p=0.024 vs control group). The liver weight decreased in a dose-dependent manner on day 5. The testis weights also decreased in a dose-dependent manner on day 14 and 28. All mice in the ²¹¹At-MABG-injected groups showed a dose-dependent decrease in white blood cell count on day 5 (p<0.05), which subsequently recovered to normal levels on day 28. The red blood cell and platelet counts did not change on days 14 and 28 (p=NS). Conclusion: In this study, 3.7 MBq of ²¹¹At-MABG was the LD₁₀₀ dose in single intravenous injection to normal male BALB/c mice. Mice that received 0.11-1.11 MBq of ²¹¹At-MABG showed an acute dose-dependent leukopenia on day 5 and recovery of white blood cell count to normal level on day 28. No evidence of erythrocytopenia or thrombocytopenia was noted in the dose range from 0.11 to 1.11 MBq of ²¹¹At-MABG on days 14 and 28.