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Purpose <p>Accurate diagnosis of hepatocellular carcinoma (HCC) remains a clinical challenge. Glypican-3 (GPC3) is highly expressed in HCC but not in normal liver tissue, making it a promising target for PET-based molecular imaging, which may complement existing approaches for HCC diagnosis. In this study, we developed a new GPC3-targeted immunoPET radiotracer for noninvasive visualization of GPC3 expression and conducted a first-in-human, proof-of-concept evaluation in patients with HCC to assess its clinical feasibility.</p> Methods <p>An anti-GPC3 antigen-binding fragment (Fab) was generated under Good Manufacturing Practice conditions and labeled with Gallium-68 (<sup>68</sup>Ga) to obtain [<sup>68</sup>Ga]Ga-aGPC3-Fab. In vitro assays, small-animal PET/CT scans, and ex vivo biodistribution experiments were conducted to examine its GPC3 targeting ability. Five patients with radiologically suspected or diagnosed HCC were enrolled in a pilot clinical study and underwent [<sup>68</sup>Ga]Ga-aGPC3-Fab PET imaging. Radiotracer uptake in tumor and non-tumor tissues was quantitatively analyzed.</p> Results <p>[<sup>68</sup>Ga]Ga-aGPC3-Fab was synthesized with high radiochemical purity and demonstrated strong affinity and efficient internalization in GPC3-positive cells. It enabled clear tumor visualization in both subcutaneous and orthotopic GPC3-positive HCC mouse models. All five patients tolerated the PET procedure well, with no adverse effects. [<sup>68</sup>Ga]Ga-aGPC3-Fab successfully detected intrahepatic metastases approximately 1&#xa0;cm in diameter with high imaging contrast, including lesions that missed on magnetic resonance imaging.</p> Conclusion <p>[<sup>68</sup>Ga]Ga-aGPC3-Fab demonstrated a favorable safety profile and enabled effective visualization of GPC3-positive lesions. It may serve as a complementary approach to conventional imaging to improve the diagnostic accuracy of HCC.</p> Clinical trial registration <p>ClinicalTrials.gov, NCT06383520. Registered on April 25, 2024 (<a href="https://clinicaltrials.gov/study/NCT06383520">https://clinicaltrials.gov/study/NCT06383520</a>).</p>

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Glypican-3-targeted immunoPET imaging of hepatocellular carcinoma: a translational study

  • 期刊论文

  • 发表日期：

    2026年2月14日

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  • Zhaoguo Lin,
  • Wenzhu Hu,
  • Mengting Li,
  • Zhidi Pan,
  • Yuan Feng,
  • Xiao Zhang,
  • Biao Yang,
  • Yongkang Gai,
  • Dawei Jiang,
  • Jianwei Zhu,
  • Xiong Cai,
  • Xiaoli Lan

摘要

Purpose

Accurate diagnosis of hepatocellular carcinoma (HCC) remains a clinical challenge. Glypican-3 (GPC3) is highly expressed in HCC but not in normal liver tissue, making it a promising target for PET-based molecular imaging, which may complement existing approaches for HCC diagnosis. In this study, we developed a new GPC3-targeted immunoPET radiotracer for noninvasive visualization of GPC3 expression and conducted a first-in-human, proof-of-concept evaluation in patients with HCC to assess its clinical feasibility.

Methods

An anti-GPC3 antigen-binding fragment (Fab) was generated under Good Manufacturing Practice conditions and labeled with Gallium-68 (68Ga) to obtain [68Ga]Ga-aGPC3-Fab. In vitro assays, small-animal PET/CT scans, and ex vivo biodistribution experiments were conducted to examine its GPC3 targeting ability. Five patients with radiologically suspected or diagnosed HCC were enrolled in a pilot clinical study and underwent [68Ga]Ga-aGPC3-Fab PET imaging. Radiotracer uptake in tumor and non-tumor tissues was quantitatively analyzed.

Results

[68Ga]Ga-aGPC3-Fab was synthesized with high radiochemical purity and demonstrated strong affinity and efficient internalization in GPC3-positive cells. It enabled clear tumor visualization in both subcutaneous and orthotopic GPC3-positive HCC mouse models. All five patients tolerated the PET procedure well, with no adverse effects. [68Ga]Ga-aGPC3-Fab successfully detected intrahepatic metastases approximately 1 cm in diameter with high imaging contrast, including lesions that missed on magnetic resonance imaging.

Conclusion

[68Ga]Ga-aGPC3-Fab demonstrated a favorable safety profile and enabled effective visualization of GPC3-positive lesions. It may serve as a complementary approach to conventional imaging to improve the diagnostic accuracy of HCC.

Clinical trial registration

ClinicalTrials.gov, NCT06383520. Registered on April 25, 2024 (https://clinicaltrials.gov/study/NCT06383520).