Purpose: This study aims to develop and evaluate a novel Glypican-3 (GPC3)-targeted single-chain variable fragment (scFv)-based PET radiotracer for noninvasive assessment of GPC3 expression and precise diagnosis of hepatocellular carcinoma (HCC) in both preclinical models and a first-in-human clinical study.
Experimental design: The novel anti-GPC3 scFv, namely XH-06, was labeled with Gallium-68 (68Ga) to obtain [68Ga]Ga-XH-06. Cell uptake assays, small-animal PET imaging, and biodistribution studies were performed to evaluate its targeting ability. In the first-in-human study, 8 patients with suspected HCC underwent [68Ga]Ga-XH-06 PET/magnetic resonance imaging (PET/MR). Radiotracer uptake in tumors and normal tissues was quantified, and tumor-to-blood ratios (TBR) and tumor-to-liver ratios (TLR) were calculated.
Results: [68Ga]Ga-XH-06 was synthesized with high radiochemical purity and exhibited specific uptake and efficient internalization in GPC3-positive cells. In subcutaneous and orthotopic animal models, [68Ga]Ga-XH-06 effectively visualized HCC tumors. Eight patients underwent [68Ga]Ga-XH-06 PET/MR scans and no adverse events were observed. The radiotracer successfully detected HCC lesions, including sub-centimeter tumors, with high imaging contrast. Among 7 patients with HCC, the median maximum standardized uptake value (SUVmax) of the lesions was 16.9 (range, 8.2-51.8), the median TLR was 6.2 (range, 2.8-24.7) and the median TBR was 16.6 (range, 3.0-57.6) at 2.5 h post-injection.
Conclusions: [68Ga]Ga-XH-06 is clinically promising for detecting GPC3-positive HCC with a favorable safety profile. Further investigation is warranted to validate the clinical value of GPC3-targeted PET imaging in HCC management.