Research & Teaching Faculty

Glypican-3 targeted thorium-227 alpha therapy reduces tumor burden in an orthotopic xenograft murine model of hepatocellular carcinoma

TitleGlypican-3 targeted thorium-227 alpha therapy reduces tumor burden in an orthotopic xenograft murine model of hepatocellular carcinoma
Publication TypeJournal Article
Year of Publication2022
AuthorsLabadie, KP, Hamlin, DK, Kenoyer, A, Daniel, SK, Utria, AF, Ludwig, AD, Kenerson, HL, LI, LILY, Sham, JG, Chen, DL, Orozco, JJ, Yeung, RS, Orvig, C, Li, Y, D Wilbur, S, Park, JO
JournalJ. Nucl. Med.
Date Published11/2021

Hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality worldwide with limited therapeutic options for advanced disease. Targeted alpha therapy (TAT) is an emerging class of targeted cancer therapy in which alpha-particle-emitting radionuclides, such as thorium-227, are specifically delivered to cancer tissue. Glypican-3 (GPC3) is a cell surface glycoprotein highly expressed on HCC. In this study, we describe the development and in vivo efficacy of a 227Th-labeled GPC3 targeting antibody conjugate (227Th-octapa-αGPC3) for treatment of HCC in an orthotopic murine model. METHODS: The chelator p-SCN-Bn-H4octapa-NCS (octapa) was conjugated to a GPC3 targeting antibody (αGPC3) for subsequent 227Th radiolabeling (octapa-αGPC3). Conditions were varied to optimize radiolabeling of 227Th. In vitro stability was evaluated by measuring percentage of protein-bound 227Th by gamma-ray spectroscopy. An orthotopic athymic Nu/J murine model using HepG2 cells was developed. Biodistribution and blood clearance of 227Th-octapa-αGPC3 was evaluated in tumor bearing mice. Efficacy of 227Th-octapa-αGPC3 was assessed in tumor bearing animals with serial measurement of serum alpha-fetoprotein at 23 days after radionuclide injection. RESULTS: Octapa-conjugated αGPC3 provided up to 70% 227Th labeling yield in 2 h at room temperature. In the presence of ascorbate, >=97.8% of 227Th was bound to αGPC3-octapa after 14 d in phosphate buffered saline. In HepG2 tumor-bearing mice, highly specific GPC3 targeting was observed, with significant 227Th-octapa-αGPC3 accumulation in the tumor over time and minimal accumulation in normal tissue. 23 days after treatment, significant reduction in tumor burden was observed in mice receiving 500 kBq/kg 227Th-octapa-αGPC3 by tail vein injection. No acute off-target toxicity was observed and no animals died prior to termination of the study. CONCLUSION: 227Th-octapa-αGPC3 was observed to be stable in vitro, maintain high specificity for GPC3 with favorable biodistribution in vivo, and result in significant antitumor activity without significant acute off-target toxicity in an orthotopic murine model of HCC.

Refereed DesignationRefereed