Abstract 1610: Development of meta-[211At]astatobenzylguanidine ([211At]MABG) as an alpha particle emitting systemic targeted radiotherapeutic for neuroblastoma
Authors: Batra Vandana , Ranieri Pietro , Makvandi Mehran , Tsang Matthew , Hou Catherine , Li Yimei , Vaidyanathan Ganesan , Pryma Daniel A. , Maris John M. 
Published: August 2015

BACKGROUND Neuroblastoma (NB) is a radiosensitive malignancy and NB cells express the norepinephrine transporter (NET) enabling uptake of NET ligands. The majority of relapsed NBs remain sensitive to radiation therapy even after extensive therapy. The currently employed targeted radiotherapeutic [131I]MIBG is a highly active β -particle emitting NET ligand useful for cytoreduction of bulk tumor. However, [131I]MIBG does not target isolated tumor cells, and thus targeted radiotherapy with [211At]MABG (α-particle emitter with higher biological effectiveness) can address this critical problem due to the short path length that should lead to the killing of isolated tumor cells.

METHODS 211At was synthesized using a bismuth target via the 209Bi(α,2n)211At reaction and used for solid-phase radiosynthesis of [211At]MABG. Cellular models were created by first determining NET (SLC6A2) mRNA and protein expression in 35 human NB cell lines, and then creating isogenic pairs by forced overexpression of NET in 4 NB cell models. We then performed [211At]MABG uptake assays, as well as biodistribution experiments, using these models. We are defining the toxicity of [211At]MABG in mice via ongoing dose escalation and monitoring laboratory parameters every 3 weeks after dosing. A linear mixed effects model was used to determine the differences in the parameters between the treated groups and controls. Finally, clonogenic assays and therapeutic trials in mouse models comparing [131I]MIBG with [211At]MABG are ongoing.

RESULTS We synthesized [211At]MABG (radiochemical yield of 25-50%, radiochemical purity &gt; 99%) and showed NET-specific uptake in NB1691 cells. Specificity was demonstrated by competition assays with the blocking agent desipramine. NET-overexpressing cell lines showed 4-10 fold higher uptake of NET ligands than parental isogenic lines, and demonstrated tumor-specific [211At]MABG uptake in vivo with tumor-muscle ratios of 7.37. Toxicity studies have shown that doses of 10 and 25 uCi of [211At]MABG were well tolerated, but there was weight loss observed at higher doses (P = 0.01). There was also an expected trend towards thrombocytopenia (P = 0.06), but no detectable impact on white blood cell counts, (P = 0.74), hemoglobin (P = 0.41), bilirubin (P = 0.53) or creatinine (P = 0.10). Clonogenic assays show [211At]MABG to be potently cytotoxic (1000 fold higher than [131I]MIBG), and murine efficacy studies are ongoing.

CONCLUSIONS We have synthesized 211At-MABG in quantities sufficient for our preclinical experiments, and will scale this up for clinical applications. The uptake and biodistribution of [211At]MABG is similar to the currently used radiotherapeutic [131I]MIBG, and to date there was no unanticipated toxicity. Preliminary results from clonogenic assays suggest that [211At]MABG may be an effective agent for salvage therapy for children with refractory/relapsed NB.

Citation Format: Vandana Batra, Pietro Ranieri, Mehran Makvandi, Matthew Tsang, Catherine Hou, Yimei Li, Ganesan Vaidyanathan, Daniel A. Pryma, John M. Maris. Development of meta-[211At]astatobenzylguanidine ([211At]MABG) as an alpha particle emitting systemic targeted radiotherapeutic for neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1610. doi:10.1158/1538-7445.AM2015-1610