Abstract 2583: [68Ga]Ga-RYZ-GPC3: A glypican-3 targeted diagnostic radiopharmaceutical for hepatocellular carcinoma molecular imaging
Authors: Braat Arthur J.A.T. , Poot Alex J. , Lapa Constantin , Lam Marnix G.E.H. , Weber Wolfgang A. , Karmann Anna , Yuan Ye , Rearden Jessica , Song Ken , Bundschuh Ralph A. 
Published: March 2024

Abstract
Introduction & Purpose: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. To date, the imaging of HCC is difficult, insufficient for disease staging and barely improved over the past decades. Glypican-3 (GPC3) is a cell-surface receptor highly expressed by HCC and of diagnostic and prognostic value. GPC3 has been reported as potential target for diagnosis and treatment of HCC for nuclear theranostics. RYZ-GPC3 is a DOTA modified macrocyclic peptide with high affinity for GPC3, which may allow PET imaging or nuclear therapy. Here we report the first clinical results of [68Ga]Ga-RYZ-GPC3 PET-imaging in patients with known or suspected HCC.
Methods: [68Ga]Ga-RYZ-GPC3 was obtained upon labeling the peptide precursor with 68Ga from a 68Ge/68Ga-generator and heating till 90⁰C for 10 min followed by sterile filtration. After administration of 2 MBq/kg [68Ga]Ga-RYZ-GPC3, a 60 min dynamic PET scan was acquired or multiple static PET/CT were acquired at 20 min, 1, 2 and 4 hours. Besides qualitative interpretation, standardized uptake values (SUVmax, SUVmean) were measured in various compartments; HCC lesions, healthy liver (HL), kidneys, blood pool activity in the left ventricle (BP) and gastric fundus. Additionally, tumor-to-healthy liver ratios (TLR) were calculated: SUVmean,HCC divided by SUVmean,HL.
Results: Radiolabeling to obtain [68Ga]Ga-RYZ-GPC3 was near quantitative, making the production highly reliable. Eleven patients (4 patients dynamic; 7 patients static protocol) were scanned. One patient did not have an HCC. Another patient had a concurrent metastatic prostate adenocarcinoma, which did not show uptake, both qualitatively and quantitatively. All HCC lesions showed uptake in qualitative assessment, even in immunohistochemistry confirmed GPC3-negative HCC lesions (3 lesions). In 23 HCC lesions, including the aforementioned GPC3-negative lesions, mean SUVmax was 17.9 (range 2.7-95.3) and mean SUVmean was 10.2 (range 1.0-49.2) at 60 minutes. Uptake in HL and BP decrease over time and become negligible 45 minutes after administration (SUVmean &lt;1.5). The opposite occurs for HCC and TLR, which continuously increase up to 4 hours after administration (TLR 4.4 to 19.2, at 18 minutes and 4 hours respectively). In individual lesion analysis, TLR was the highest at 60 or 120 minutes post-injection scans. Uptake in the gastric fundus, gradually increases in the first hour, and decreases gradually afterwards (SUVmean from 4.0 to 12.7, back to 10.1).
Conclusions: [68Ga]Ga-RYZ-GPC3 is the first peptide based PET tracer that allows the high quality molecular imaging of HCC. Thereby [68Ga]Ga-RYZ-GPC3 is suitable for the selective diagnosis of HCC. In addition, based on the biodistribution and in vivo dynamics on these diagnostic images, RYZ-GPC3 is very likely to hold therapeutic potential upon labeling with a therapeutic isotope (e.g 177Lu or 225Ac).
Citation Format: Arthur J.A.T. Braat, Alex J. Poot, Constantin Lapa, Marnix G.E.H. Lam, Wolfgang A. Weber, Anna Karmann, Ye Yuan, Jessica Rearden, Ken Song, Ralph A. Bundschuh. [68Ga]Ga-RYZ-GPC3: A glypican-3 targeted diagnostic radiopharmaceutical for hepatocellular carcinoma molecular imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2583.