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Hepato-pancreato-biliary

E226: Human Glypican-3-Targeted Zirconium-89 Immuno-Positron Emission Tomography for Hepatocellular Carcinoma

Introduction:

Early recurrence following surgical resection, a mainstay curative treatment for hepatocellular carcinoma (HCC), is due to missed subcentimeter lesions on current diagnostic imaging. Glypican-3 (GPC3)-targeted immuno-positron emission tomography (immunoPET) offers earlier, more accurate HCC detection which may mitigate this frequent problem. This study compared the efficacy of our previously validated zirconium-89-labeled murine antibody targeting GPC3 (89Zr-αGPC3M) with our newly humanized antibody (89Zr-αGPC3H) to be used in clinical trials.

Methods:

A pilot preclinical study was performed. In vitro binding of αGPC3H to HepG2 cells was assessed by flow cytometry. An orthotopic xenograft mouse model of HCC was generated by injecting HepG2 cells into the left hepatic lobe via laparotomy. After estimation of tumor establishment using bioluminescent imaging (BLI), retro-orbital injections of 89Zr-αGPC3H or 89Zr-αGPC3M were performed. 89Zr-αGPC3H targeting was evaluated by small-animal PET/CT, biodistribution studies, and histopathologic analysis.

Results:

Flow cytometry confirmed binding of unconjugated αGPC3H to cell surface GPC3 on HepG2 cells. Five of six mice injected with 89Zr-αGPC3H and 89Zr-αGPC3M, respectively, demonstrated discrete hepatic localizations of increased PET intensity consistent with tumors, with no difference between groups in mean bioluminescence (4.8x108 vs 6.3x108 photon/sec, p=0.75). Tumor radioisotope uptake (97 vs 61 percent injected dose (%ID)/mL, p=0.42) and tumor-to-liver ratios of %ID/mL (12 vs 11, p=0.68) calculated from PET/CT analysis were not significantly different between 89Zr-αGPC3H and 89Zr-αGPC3M-injected mice. Gamma counter-measured tumor uptake (%ID/g) for biodistribution analysis was 7-fold greater than other organs, with no significant difference between groups in organ uptake (mean 23 vs 22 %ID/g, p=0.96) or tumor-to-liver ratio of %ID/g (22 vs 24, p=0.94). Tumor uptake and tumor-to-liver ratios from PET/CT and biodistribution analyses were over three times higher than reported for other humanized radiolabeled antibodies targeting GPC3. Histopathologic analysis confirmed PET-identified tumors.

Conclusions:

αGPC3H demonstrated equivalent HepG2 cell (αGPC3) and tumor (89Zr-αGPC3) binding compared with αGPC3M. Humanized 89Zr-αGPC3 immunoPET successfully targeted GPC3 in vivo in an orthotopic xenograft mouse model, furthering clinical translation towards a theranostic platform strategy for HCC detection and treatment.

Learning Objectives:

  • Upon completion, participant will be able to describe limitations of current diagnostic imaging for hepatocellular carcinoma (HCC) detection.
  • Upon completion, participant will be able to compare the efficacy of a humanized zirconium-89 (89Zr)-labeled antibody targeting glypican-3 (GPC3) with the previously validated murine version of the antibody.
  • Upon completion, participant will be able to critically analyze the clinical applicability of 89Zr-anti-GPC3 immuno-positron emission tomography (immunoPET) for HCC detection and treatment.