Glypican-3 as a Theranostic Target in Hepatocellular Carcinoma

Glypican-3 (GPC3) has emerged as an attractive molecular target for the imaging and therapy of hepatocellular carcinoma (HCC). It is highly expressed in most tumors but shows no or minimal expression in the normal adult liver and cirrhosis. This expression profile has stimulated the parallel development of GPC3-directed antibodies, antibody-drug conjugates, cellular immunotherapies, molecular imaging agents, and therapeutic radiopharmaceuticals. Early clinical imaging studies with radiolabeled antibodies established proof of principle that GPC3 can be visualized with PET imaging while also highlighting the pharmacokinetic limitations of full-size antibodies for liver imaging. More recent approaches using antibody fragments, single-domain antibodies, single-chain variable fragments, and macrocyclic peptides have substantially improved imaging contrast at earlier time points and have enabled first-in-human PET studies in patients with HCC and hepatoblastoma. These studies indicate the feasibility of GPC3-targeted radiopharmaceutical therapy but have also demonstrated intrapatient and interpatient heterogeneity of target expression, emphasizing the need for pretherapeutic imaging of GPC3 expression before therapeutic interventions. Thus, GPC3 imaging could contribute not only to the diagnosis and staging of HCC but also to treatment monitoring and the selection of patients for GPC3-targeted therapies. A clinical phase 1 trial with an ²²⁵Ac-labeled macrocyclic peptide ([²²⁵Ac]Ac-RAYZ-8009, RYZ801) using PET with [⁶⁸Ga]Ga-RAYZ-8009 (RYZ811) for patient selection is currently ongoing. Furthermore, an ²²⁵Ac-labeled GPC3 antibody, BAY 3547926, is undergoing phase 1/2 clinical testing.