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

Purpose: [I-131]meta-iodobenzylguanidine ([I-131]MIBG) is a targeted radiotherapeutic administered systemically to deliver beta particle radiation in neuroblastoma. However, relapses in the bone marrow are common. [At-211]meta-astatobenzylguanidine ([At-211] MABG) is an alpha particle emitter with higher biological effective-ness and short path length which effectively sterilizes microscopic residual disease. Here we investigated the safety and antitumor activity [At-211]MABG in preclinical models of neuroblastoma. Experimental Design: We defined the maximum tolerated dose (MTD), biodistribution, and toxicity of [At-211]MABG in immuno-deficient mice in comparison with [I-131]MIBG. We compared the antitumor efficacy of [At-211]MABG with [I-131]MIBG in three murine xenograft models. Finally, we explored the efficacy of [At-211]MABG after tail vein xenografting designed to model disseminated neuroblastoma. Results: The MTD of [At-211]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) Il2rgt(m1Wjl)/SzJ (NSG) mice. Biodistribution of [At-211]MABG was similar to [I-131]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) x 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) x 4 doses over 11 days [At-211]MABG in the disseminated disease (IMR-05(NET/GFP/LUC)) model (P = 0.003) suggesting eradication of microscopic disease. Conclusions: [At-211]MABG has significant survival ad-vantage in disseminated models of neuroblastoma. An alpha particle emitting radiopharmaceutical may be effective against microscopic disseminated disease, warranting clinical development.

Automated summary

This study investigated the safety and antitumor activity of [At-211]MABG in neuroblastoma, and found that it has significant survival advantage and can effectively eradicate microscopic residual disease. An alpha particle emitting radiopharmaceutical may be effective against disseminated disease.