Glypican-3: Novel Theranostic Agent for Hepatocellular Carcinoma.

IF 5.9 2区 医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING
Luca Filippi
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Abstract

Glypican-3 (GPC3) is a membrane-anchored heparan sulfate proteoglycan overexpressed in many hepatocellular carcinomas (HCCs) while minimally present in normal adult liver, making it an attractive target for integrated diagnostic and therapeutic ("theranostic") strategies. This review synthesizes preclinical and early clinical efforts to exploit GPC3 for targeted PET imaging and radionuclide therapy. Imaging approaches have evolved from 89Zr- and 124I-labeled full antibodies-demonstrating robust, delayed tumor localization-to smaller scaffolds (F(ab')₂, single-domain antibodies, peptides) paired with 18F or 68Ga for same-day, high-contrast imaging. First-in-human studies, including 124I-codrituzumab and 68Ga-RAYZ-8009, confirmed tumor-specific accumulation but remained limited in scale. Therapeutic investigations spanned beta-emitters (90Y, 177Lu) and high-LET alpha-emitters (225Ac, 227Th), showing potent antitumor effects in orthotopic and xenograft models yet raising dosimetric and toxicity concerns-especially for long-circulating antibody carriers and alpha therapies. Key translational challenges include hepatic background clearance, intra-patient heterogeneity of GPC3 expression, rigorous dosimetry, toxicology in larger species, and radionuclide supply logistics. The available evidence suggests a preferential pathway, involving the selection of a limited set of lead vectors, their pairing with suitable radionuclides, validation in orthotopic/PDX models using standardized endpoints, and the integration of comprehensive dosimetric and toxicologic studies before proceeding to broader human trials. GPC3-directed theranostics thus offers a compelling, disease-specific route to precision management of HCC, provided translational rigor addresses the outlined safety and quantitative imaging gaps.

Glypican-3:一种新的肝细胞癌治疗剂。
Glypican-3 (GPC3)是一种膜锚定的硫酸肝素蛋白多糖,在许多肝细胞癌(hcc)中过表达,而在正常成人肝脏中含量极低,使其成为综合诊断和治疗(“治疗”)策略的一个有吸引力的靶点。本文综述了利用GPC3靶向PET成像和放射性核素治疗的临床前和早期临床工作。成像方法已经从89Zr-和124i标记的全抗体(显示稳健的,延迟的肿瘤定位)发展到较小的支架(F(ab') 2,单域抗体,肽)与18F或68Ga配对,进行当日高对比度成像。包括124I-codrituzumab和68Ga-RAYZ-8009在内的首次人体研究证实了肿瘤特异性积累,但规模仍然有限。治疗研究跨越β -发射体(90Y, 177Lu)和高α -发射体(225Ac, 227),显示出在原位和异种移植模型中有效的抗肿瘤作用,但引起了剂量学和毒性问题,特别是对于长循环抗体携带者和α -治疗。关键的翻译挑战包括肝脏背景清除、患者内部GPC3表达的异质性、严格的剂量学、大型物种的毒理学和放射性核素供应物流。现有证据表明有一条优先途径,包括选择一组有限的先导载体,将其与合适的放射性核素配对,使用标准化终点在原位/PDX模型中进行验证,以及在进行更广泛的人体试验之前整合综合剂量学和毒理学研究。因此,gpc3导向的治疗为HCC的精确治疗提供了一条引人注目的、针对特定疾病的途径,前提是翻译的严密性解决了概述的安全性和定量成像差距。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Seminars in nuclear medicine
Seminars in nuclear medicine 医学-核医学
CiteScore
9.80
自引率
6.10%
发文量
86
审稿时长
14 days
期刊介绍: Seminars in Nuclear Medicine is the leading review journal in nuclear medicine. Each issue brings you expert reviews and commentary on a single topic as selected by the Editors. The journal contains extensive coverage of the field of nuclear medicine, including PET, SPECT, and other molecular imaging studies, and related imaging studies. Full-color illustrations are used throughout to highlight important findings. Seminars is included in PubMed/Medline, Thomson/ISI, and other major scientific indexes.
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