Preclinical Development of [(211)At]meta- astatobenzylguanidine ([(211)At]MABG) as an Alpha Particle Radiopharmaceutical Therapy for Neuroblastoma

PURPOSE: [(131)I]meta-iodobenzylguanidine ([(131)I]MIBG) is a targeted radiotherapeutic administered systemically to deliver beta particle radiation in neuroblastoma. However, relapses in the bone marrow are common. [(211)At]meta-astatobenzylguanidine ([(211)At] MABG) is an alpha particle emitter with higher biological effectiveness and short path length which effectively sterilizes microscopic residual disease. Here we investigated the safety and antitumor activity [(211)At]MABG in preclinical models of neuroblastoma. EXPERIMENTAL DESIGN: We defined the maximum tolerated dose (MTD), biodistribution, and toxicity of [(211)At]MABG in immunodeficient mice in comparison with [(131)I]MIBG. We compared the antitumor efficacy of [(211)At]MABG with [(131)I]MIBG in three murine xenograft models. Finally, we explored the efficacy of [(211)At]MABG after tail vein xenografting designed to model disseminated neuroblastoma. RESULTS: The MTD of [(211)At]MABG was 66.7 MBq/kg (1.8 mCi/kg) in CB17SC scid(−/−) mice and 51.8 MBq/kg (1.4 mCi/kg) in NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ (NSG) mice. Biodistribution of [(211)At]MABG was similar to [(131)I]MIBG. Long-term toxicity studies on mice administered with doses up to 41.5 MBq/kg (1.12 mCi/kg) showed the radiotherapeutic to be well tolerated. Both 66.7 MBq/kg (1.8 mCi/kg) single dose and fractionated dosing 16.6 MBq/kg/fraction (0.45 mCi/kg) × 4 over 11 days induced marked tumor regression in two of the three models studied. Survival was significantly prolonged for mice treated with 12.9 MBq/kg/fraction (0.35 mCi/kg) × 4 doses over 11 days [(211)At]MABG in the disseminated disease (IMR-05(NET/GFP/LUC)) model (P = 0.003) suggesting eradication of microscopic disease. CONCLUSIONS: [(211)At]MABG has significant survival advantage in disseminated models of neuroblastoma. An alpha particle emitting radiopharmaceutical may be effective against microscopic disseminated disease, warranting clinical development.