Glypican-3: Novel Theranostic Agent for Hepatocellular Carcinoma

Glypican-3 (GPC3) is a membrane-anchored heparan sulfate proteoglycan overexpressed in many hepatocellular carcinomas (HCCs) while minimally present in normal adult liver, making it an attractive target for integrated diagnostic and therapeutic ("theranostic") strategies. This review synthesizes preclinical and early clinical efforts to exploit GPC3 for targeted PET imaging and radionuclide therapy. Imaging approaches have evolved from 89Zr- and 124I-labeled full antibodies—demonstrating robust, delayed tumor localization—to smaller scaffolds (F(ab')₂, single-domain antibodies, peptides) paired with 18F or 68Ga for same-day, high-contrast imaging. First-in-human studies, including 124I-codrituzumab and 68Ga-RAYZ-8009, confirmed tumor-specific accumulation but remained limited in scale. Therapeutic investigations spanned beta-emitters (90Y, 177Lu) and high-LET alpha-emitters (225Ac, 227Th), showing potent antitumor effects in orthotopic and xenograft models yet raising dosimetric and toxicity concerns—especially for long-circulating antibody carriers and alpha therapies. Key translational challenges include hepatic background clearance, intra-patient heterogeneity of GPC3 expression, rigorous dosimetry, toxicology in larger species, and radionuclide supply logistics. The available evidence suggests a preferential pathway, involving the selection of a limited set of lead vectors, their pairing with suitable radionuclides, validation in orthotopic/PDX models using standardized endpoints, and the integration of comprehensive dosimetric and toxicologic studies before proceeding to broader human trials. GPC3-directed theranostics thus offers a compelling, disease-specific route to precision management of HCC, provided translational rigor addresses the outlined safety and quantitative imaging gaps.