Octapharma AG, founded in 1983, is a family-owned pharmaceutical company, and bills itself as "one of the largest human protein manufacturers in the world, developing and producing human proteins from human plasma and human cell lines[3]."
Introduction Neuroblastoma (NBL) is the most common extracranial solid tumor in children and accounts for a disproportionate number of pediatric cancer deaths. Despite intensive multimodal therapy, patients with high-risk or relapsed disease continue to face poor outcomes due to metastatic relapse. Targeted radioligand therapy (RLT) using β-emitters such as [177Lu]Lu-DOTATATE targeting Somatostatin Receptor-2 (SSTR2) has shown encouraging results; however, its efficacy against minimal residual disease, single metastatic cells, and micrometastases remains limited. α-emitting radionuclides, characterized by higher linear energy transfer (LET) and shorter range in tissue, offer the potential to overcome these limitations and enhance the cytotoxic effect of RLT. Objectives This study aimed to perform preclinical assessment of [225Ac]Ac-DOTATATE as a therapeutic potential in SSTR2-expressing neuroblastoma model. Materials and Methods [225Ac]Ac-DOTATATE was radiolabeled and evaluated for stability. Receptor specificity was confirmed in vitro using the SSTR2-expressing cell line. Biodistribution studies were also performed on non-tumor bearing mice and IMR-32-LUC xenograft-bearing nude mice up to 7 days post-injection followed by dosimetry calculations of absorbed dose. To evaluate therapeutic efficacy, IMR-32-LUC tumor-bearing mice (n ≥ 10) received a single administration of 60 kBq or 120 kBq [225Ac]Ac-DOTATATE. Treatment outcomes were compared with single administration of 25 MBq [177Lu]Lu-DOTATATE or unlabeled DOTATATE as control. Results [225Ac]Ac-DOTATATE was successfully radiolabeled and demonstrated high yield, purity and stability. In vitro assays confirmed specific binding to SSTR2 positive IMR-32-LUC cells. In vivo biodistribution studies in mice, carrying neuroblastoma xenografts, demonstrated tumor-specific uptake, with a pharmacokinetic profile comparable to [177Lu]Lu-DOTATATE. In the therapy experiments, both radioligands caused rapid tumor shrinkage; however, tumor regrowth was significantly delayed in [225Ac]Ac-DOTATATE treated mice compared to [177Lu]Lu-DOTATATE treated mice. For equal absorbed dose administered activities for [225Ac]Ac-DOTATATE (120kBq) and [177Lu]Lu-DOTATATE (25MBq), the alpha-emitting compound prolonged time to regression and significantly improved survival. Conclusion [225Ac]Ac-DOTATATE displayed high stability, receptor selectivity, and potent therapeutic efficacy in neuroblastoma models, supporting its further development as a targeted alpha therapy for high-risk and metastatic neuroblastoma. Funding Acknowledgements FS, TT, JS, MN: monetary support for the pre-clinical research project "Pre-clinical assessment of 225Ac-DOTATATE therapy for eradication of dormant metastatic cells in pediatric high-risk neuroblastoma” is provided by Advanced Accelerator Applications / Novartis.
