Abstract 6019: Biodistribution, molecular imaging and efficacy evaluation of a novel GPC3-targeted radiopharmaceutical therapy for hepatocellular carcinoma
Authors: Lin Fanching , Clift Renee , Horton Steven , Guest Matt , Noncovich Alain , Bhat Abhijit , Ballal Sanjana , Bal Chandrasekhar , Shah Kathryn , Karmann Anna , Li Gary 
Published: March 2024

Introduction: Glypican-3 (GPC3) is a membrane-anchored oncofetal protein with minimal expression in normal tissues. Significant upregulation of GPC3 protein has been observed in the majority of hepatocellular carcinomas (HCC), and is associated with poor prognosis. The differential expression of GPC3 between tumor and normal tissues provides an opportunity for targeted radiopharmaceutical therapy (RPT) to treat HCC, a leading cause for cancer-related deaths worldwide.

Methods: The novel RPT agent RYZ-GPC3 comprises a small macrocyclic peptide binder with high affinity to GPC3 linked with a tetraxetan moiety capable of chelating a variety of radioisotopes. The affinity of peptide binders to GPC3 was determined by surface plasma resonance (SPR) and radioligand binding assays. Cellular internalization was radiometrically measured at multiple time points. Non-human primate (NHP) PET imaging was performed with 64Cu. In vivo biodistribution, monotherapy and combination treatments with 177Lu or 225Ac were performed in HCC xenografts. Human imaging was conducted in HCC patients with 68Ga PET/CT.

Results: The novel agent is a highly potent (KD=0.7 nM) and selective peptide binder to GPC3 of human, mouse, canine and NHP origins, and is compatible with multiple radiometal isotopes. In vivo biodistribution study of [177Lu]Lu-RYZ-GPC3 in HCC xenografts showed sustained tumor uptake of 16.6, 16.4, and 8.8 %ID/g at 24, 48, and 96 hours with fast renal clearance, resulting in favorable tumor/kidney ratios of 3.6, 10.2, and 13.0, respectively. Minimal or no uptake was observed in other normal tissues. PET imaging in NHP confirmed absence of on-target uptake by liver or other organs, and fast renal clearance. As monotherapy, durable (&gt;60 days) tumor regression (TGI&gt;100%) was achieved with 177Lu (111 MBq)- and 225Ac (0.111 MBq)-labeled RYZ-GPC3. At 10x lower injected activity, 177Lu- and 225Ac-labeled RYZ-GPC3 significantly improved anti-tumor effect of lenvatinib in multiple HCC models. Furthermore, PET/CT imaging in a 70-year-old patient with histologically proven HCC demonstrated distinct and avid [68Ga]Ga-RYZ-GPC3 tumor uptake.

Conclusion: Preclinical data and preliminary human imaging demonstrate the potential of the novel binder as a theranostic agent for the treatment of patients with GPC3+ HCC.

Citation Format: Fanching Lin, Renee Clift, Steven Horton, Matt Guest, Alain Noncovich, Abhijit Bhat, Sanjana Ballal, Chandrasekhar Bal, Kathryn Shah, Anna Karmann, Gary Li. Biodistribution, molecular imaging and efficacy evaluation of a novel GPC3-targeted radiopharmaceutical therapy for hepatocellular carcinoma [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 6019.