Glypican-3-Targeted 89Zr PET Imaging of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a devastating malignancy in which imperfect imaging plays a primary role in diagnosis. Glypican-3 (GPC3) is an HCC-specific cell surface proteoglycan overexpressed in most HCCs. This paper presents the use of Zr-89-conjugated monoclonal antibody against GPC3 (Zr-89-alpha GPC3) for intrahepatic tumor localization using PET. Methods: Polymerase chain reaction confirmed relative GPC3 expression in cell lines. In vitro binding, in vivo biodistribution, and small-animal PET studies were performed on GPC3-expressing HepG2 and non-GPC3-expressing HLF and RH7777 cells and orthotopic xenografts. Results: Zr-89-alpha GPC3 demonstrated antibody-dependent, antigen-specific tumor binding. HepG2 liver tumors exhibited high peak uptake (836.6 +/- 86.6 percentage injected dose [% ID]/g) compared with background liver (27.5 +/- 1.6 % ID/g). Tumor-to-liver contrast ratio was high and peaked at 32.5. The smallest HepG2 tumor (, 1 mm) showed lower peak uptake (42.5 +/- 6.4 % ID/g) and tumor-to-liver contrast (1.57) but was still clearly visible on PET. Day 7 tissue activity was still substantial in HepG2 tumors (466.4 +/- 87.6 % ID/g) compared with control RH7777 tumors (3.9 +/- 1.3 % ID/g, P, 0.01), indicating antigen specificity by Zr-89-alpha GPC3. HepG2 tumor treated with unlabeled aGPC3 or heat-denatured Zr-89-alpha GPC3 demonstrated tumor activity (2.1 % ID/g) comparable to that of control xenografts, confirming antibody dependency. Conclusion: This study demonstrated the feasibility of using Zr-89-alpha GPC3 to image HCC in the liver, as well as the qualitative determination of GPC3 expression via small-animal PET. The ability to clarify the identity of small liver lesions with an HCC-specific PET probe would provide clinicians with vital information that could significantly alter patient management, warranting further investigation for clinical translation.