Oral Presentation Advances in Neuroblastoma Research Congress 2016

Preclinical characterization of meta-[211At]astatobenzylguanidine ([211At]MABG) as an alpha particle emitting systemic targeted radiotherapeutic for neuroblastoma   (#24)

Vandana Batra 1 , Mehran Makvandi 2 , Jimmy Elias 1 , Pietro Ranieri 1 , Matthew Tsang 1 , Catherine Hou 2 , Yimei Li 1 , Ganesan Vaidyanathan 3 , Daniel Pryma 2 4 , John M Maris 1 4
  1. Division of Oncology and Center for Childhood Cancer Research, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
  2. Department of Radiology, University of Pennsylvania , Phildelphia, PA, United States
  3. Department of Radiology, Duke University Medical Center, Durham, NC, United States
  4. Perelman School of Medicine, University of Pennsylvania , Phildelphia, PA, United States

BACKGROUND Neuroblastoma (NB) is a radiosensitive malignancy and NB cells express the norepinephrine transporter (NET) enabling uptake of NET ligands. [131I]MIBG (meta-iodobenzylguanidine) is a highly effective β-particle emitting NET ligand for cytoreduction of bulk tumor but does not target microscopic residual disease due to the long path lengths of the beta emission. Targeted radiotherapy with [211At]MABG (α-particle emitter with higher biological effectiveness) can address this critical problem due to the short path lengths that will kill microscopic tumor clusters.

 METHODS 211At was synthesized using a bismuth target via the 209Bi(α,2n)211At reaction and used for solid-phase radiosynthesis of [211At]MABG. We determined NET (SLC6A2) mRNA and protein expression in 35 human 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, in vivo dose escalation studies with [211At]MABG (n=10 at each dose, range 10-100 uCi) were performed to determine toxicity. Finally, therapeutic in vivo trials are ongoing.

RESULTS We synthesized [211At]MABG (radiochemical yield of 50-70%, radiochemical purity >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. Both 10 and 25 uCi of [211At]MABG were well tolerated 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). Significant tumor growth delay was seen in SKNSH NET transfected xenografts treated with 12 uCi of [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 and could be an effective retrieval strategy for patients with disseminated NB.