Peptide Binder to Glypican-3 as a Theranostic Agent for Hepatocellular Carcinoma

• DOI: 10.2967/jnumed.123.266766
• Publication Date: 2024-02-29T19:40:21Z
• Authors: Fanching Lin; Renee Clift; Takeru Ehara; Hayato Yanagida; Steven Horton; Alain Noncovich; Matt Guest; Daniel Kim; Katrina Salvador; Samantha Richardson; Terra Miller; Guangzhou Han; Abhijit Bhat; Kenneth Song; Gary Li
• Keywords: Glypican 3; Biodistribution; Internalization; Radioligand

Glypican-3 (GPC3) is a membrane-associated glycoprotein that significantly upregulated in hepatocellular carcinomas (HCC) with minimal to no expression normal tissues. The differential of GPC3 between tumor and tissues provides an opportunity for targeted radiopharmaceutical therapy treat HCC, leading cause cancer-related deaths worldwide. <b>Methods</b>: DOTA-RYZ-GPC3 (RAYZ-8009) comprises novel macrocyclic peptide binder GPC3, linker, chelator can be complexed different radioisotopes. binding affinity was determined by surface plasma resonance radioligand assays. Target-mediated cellular internalization radiometrically measured at multiple time points. In vivo biodistribution, monotherapy, combination treatments ¹⁷⁷Lu or ²²⁵Ac were performed on HCC xenografts. <b>Results:</b> RAYZ-8009 showed high protein human, mouse, canine, cynomolgus monkey origins other glypican family members. Potent confirmed GPC3-positive HepG2 cells not affected isotope switching. achieved efficient cells. Biodistribution study ¹⁷⁷Lu-RAYZ-8009 sustained uptake fast renal clearance, Tumor-specific also demonstrated orthotopic tumors, surrounding liver tissue. Therapeutically, significant durable regression survival benefit ¹⁷⁷Lu- ²²⁵Ac-labeled RAYZ-8009, as single agents lenvatinib, <b>Conclusion:</b> Preclinical in&nbsp;vitro in&nbsp;vivo data demonstrate the potential theranostic agent treatment patients HCC.