Abstract 688: Meta-[211At]astatobenzylguanidine ([211At]MABG) is a potent alpha particle emitting systemic targeted radiotherapeutic in preclinical models of neuroblastoma
Authors: Batra Vandana , Elias Jimmy , Makvandi Mehran , Tsang Matthew , Ranieri Pietro , Hou Catherine , Li Yimei , Pryma Daniel A. , Maris John M. 
Published: July 2017

BACKGROUND The alpha particle emitting radiotherapeutic [211At]MABG theoretically has superior radiobiological properties for anti-tumor efficacy compared to the currently used agent ([131I]MIBG). Specifically, [131I]MIBG does not target microscopic deposits due to the long path length of the beta particles, while alpha particles have both a short path length and higher linear energy transfer to induce clustered double strand breaks. Here we sought to define the anti-tumor activity of [211At]MABG in preclinical models of human neuroblastoma (NB).

METHODS 211At was synthesized using a bismuth target via the 209Bi(α,2n)211At reaction and used for solid-phase radiosynthesis of [211At]MABG (Ultratrace, Progenics, NY). We determined NET (SLC6A2) mRNA and protein expression in 35 NB cell lines and created isogenic pairs by overexpression of NET in 5 NB cell models. We performed uptake, cytotoxicity and biodistribution studies using these models with [131I]MIBG and [211At]MABG and extrapolated human dosimetry. Additionally, dose escalation studies with [211At]MABG (n=10 at each dose, range 10-100 uCi) were performed to determine toxicity in SCID mice. Therapeutic in vivo trials were conducted with NET transfected xenografts and patient derived xenograft (PDX) models injected intravenously with escalating doses of [211At]MABG, [131I]MIBG or vehicle (n=10 respectively).

RESULTS We now routinely synthesize [211At]MABG with a radiochemical yield of 50-70% and radiochemical purity &gt;99%. NET-overexpressing cell lines showed 4-10 fold higher uptake of NET ligands than parental isogenic lines, and tumor-specific [211At]MABG uptake (tumor-muscle ratios of 7.37). Estimated dosimetry confirmed the potential to deliver therapeutic doses to tumors. Intravenous [211At]MABG was well tolerated in murine models at doses of 10 and 25 µCi except for transient thrombocytopenia (nadir at 6 weeks; p=0.001 and p=0.0005 respectively) while doses higher than 50 uCi caused significant weight loss. [211At]MABG was a potent cytotoxic agent in vitro (EC50’s ranged from 0.0006-0.1 uCi/ml compared to 0.25-46 uCi/ml with [131I]MIBG). Single dose therapeutic trials showed significant regression of established NET overexpressing SKNSH xenograft and COG-N-453x PDX models (p&lt;0.0001) sustained for a median of 14.5 days, comparable to single dose [131I]MIBG therapy and prolonged survival was noted in mice receiving [211At]MABG.

CONCLUSIONS The biodistribution and uptake of [211At]MABG is similar to [131I]MIBG and there was no unanticipated toxicity. [211At]MABG is more potent than [131I]MIBG in vitro and the two agents showed similar activity in bulky xenograft models, remarkable due to the several log difference in half-life (7.2 hours for [211At]MABG, 8.04 days for [131I]MIBG). Additional studies exploring fractionated dosing of [211At]MABG are ongoing and will be reported.

Citation Format: Vandana Batra, Jimmy Elias, Mehran Makvandi, Matthew Tsang, Pietro Ranieri, Catherine Hou, Yimei Li, Daniel A. Pryma, John M. Maris. Meta-[211At]astatobenzylguanidine ([211At]MABG) is a potent alpha particle emitting systemic targeted radiotherapeutic in preclinical models of neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 688. doi:10.1158/1538-7445.AM2017-688