Glypican-3 Targeted Delivery Of Zr-89 And Y-90 As A Theranostic Radionuclide Platform For Hepatocellular Carcinoma

Glypican-3 (GPC3) is a tumor associated antigen expressed by hepatocellular carcinoma (HCC) cells. This preclinical study evaluated the efficacy of a theranostic platform using a GPC3-targeting antibody alpha GPC3 conjugated to zirconium-89 (Zr-89) and yttrium-90 (Y-90) to identify, treat, and assess treatment response in a murine model of HCC. A murine orthotopic xenograft model of HCC was generated. Animals were injected with Zr-89-labeled alpha GPC3 and imaged with a small-animal positron emission/computerized tomography (PET/CT) imaging system (immuno-PET) before and 30 days after radioimmunotherapy (RIT) with Y-90-labeled alpha GPC3. Serum alpha fetoprotein (AFP), a marker of tumor burden, was measured. Gross tumor volume (GTV) and SUVmax by immuno-PET was measured using fixed intensity threshold and manual segmentation methods. Immuno-PET GTV measurements reliably quantified tumor burden prior to RIT, strongly correlating with serum AFP (R-2=0.90). Serum AFP was significantly lower 30 days after RIT in Y-90-alpha GPC3 treated animals compared to those untreated (p=0.01) or treated with non-radiolabeled alpha GPC3 (p=0.02). Immuno-PET GTV measurements strongly correlated with tumor burden after RIT (R-2=0.87), and GTV of animals treated with Y-90-alpha GPC3 was lower than in animals who did not receive treatment or were treated with non-radiolabeled alpha GPC3, although this only trended toward statistical significance. A theranostic platform utilizing GPC3 targeted Zr-89 and Y-90 effectively imaged, treated, and assessed response after radioimmunotherapy in a GPC3-expressing HCC xenograft model.