Glypican-3-Targeted Paired Radiotheranostics in Orthotopic Liver Cancer Models

Abstract Purpose: Glypican-3 (GPC3), highly expressed in the most common liver cancer hepatocellular carcinoma (HCC) but absent from normal liver, represents an attractive tumor-selective target. We evaluated GPC3-targeted paired PET diagnostic and alpha particle therapeutic (radiotheranostic) agents in orthotopic models of liver cancer. Experimental Design: Using the GPC3-specific antibody codrituzumab (GC33), we engineered an immunoPET agent, [89Zr]Zr-DFO-GC33 (89Zr-GC33), and a therapeutic agent, [225Ac]Ac-Macropa-GC33 (225Ac-GC33). Binding specificity and biodistribution were assessed in orthotopic luciferase-expressing liver cancer models (HepG2 and Hep3B). Micro-scale co-localization of the pair was validated using quantitative particle identification (QPID) spectral autoradiography. Preclinical trial of therapeutic efficacy of a single 9.3 kBq administration of 225Ac-GC33 was conducted. Primary endpoints were local control, as assessed by longitudinal bioluminescence imaging (BLI) and immunoPET with 89Zr-GC33 with histological confirmation, and overall survival. Results: The biodistribution of 225Ac-GC33 closely mirrored that of 89Zr-GC33, with both agents showing high accumulation in HepG2 tumors (>200 percent injected activity per gram [%IA/g]) and high overlap in organ-level macrodistribution. Animals treated with 225Ac-GC33 showed excellent local control, including several complete pathologic responses, and improved overall survival compared to control cohorts. We also observed efficacy in orthotopic Hep3B tumors, suggesting activity even in tumors with moderate GPC3 expression. In both models, longitudinal 89Zr-GC33 immunoPET correlated with BLI. Conclusions: We show GPC3-specific PET imaging can predict and assess response to GPC3-targeted alpha particle therapy in orthotopic liver cancer models. This approach can address the unmet diagnostic and therapeutic needs for patients with liver cancer and may extend to other GPC3-expressing malignancies.