figure
posted on 2024-12-03, 08:23 authored by Peiman Habibollahi, Alexey Gurevich, James Z. Hui, Kelly Weinfurtner, George McClung, Justin Adler, Michael C. Soulen, David E. Kaplan, Gregory J. Nadolski, Stephen J. Hunt, Andrew Tsourkas, Terence P. Gade Supplementary Figure S2: GPC3 expression in HCC samples and normal adjacent liver. Sample images from immunostaining showing nearly absent GPC3 expression in normal adjacent liver (n=41) (A, B) and high GPC3 expression in HCC tumors (n=47) (C,D). 79% of the tumors (79%) stained strongly positive for GPC3 expression (Grade 3 and 4) (E). Within normal adjacent liver samples only 2 (5%) had grade 3/4 GPC3 expression compared to 79% among HCC tumor samples (F).
Funding
Radiological Society of North America (RSNA)
Society of Interventional Radiology (SIR)
Veterans Administration Research Foundation
History
ARTICLE ABSTRACT
Glypican-3 (GPC3) is a proteoglycan with high sensitivity and specificity for hepatocellular carcinoma (HCC). We describe the integrated development and validation of a GPC3-targeting optical imaging probe and T cell–redirecting antibody (TRAB) as a theranostic strategy for the detection and treatment of HCC. A novel TRAB targeting GPC3 on HCC tumor cells and the CD3 T-cell receptor as well as a distinct GPC3-specific optical imaging probe were developed from a short peptide. The efficacy of GPC3/CD3 TRAB was evaluated in vitro using IFNγ release and calcein-AM assays. Patient-derived xenografts were used to assess the in vivo efficacy of GPC3/CD3 TRAB and the GPC3 imaging probe for the detection of GPC3+ HCC. GPC3/CD3 TRAB caused a dose-dependent escalation in IFNγ release from inactive peripheral blood T cells (P = 0.001) and higher tumor-cell lysis (P = 0.01) compared with controls in vitro. Intratumorally injected GPC3/CD3 TRAB resulted in significant prolongation of tumor doubling time in the GPC3+ tumors, with an associated reduction of tumor fluorescent signal from the HiLyte 488–conjugated GPC3-specific peptide on optical imaging. These data demonstrate that HCC cell targeting using a GPC3/CD3 TRAB derived from a small peptide enabled effective T-cell activation and induction of a cytotoxic response toward GPC3+ HCC tumor cells both in vitro and in vivo. GPC3-specific optical imaging enabled the detection of the GPC3+ HCC cells and noninvasive monitoring of tumor response to adoptive immunotherapy. The integrated development of a targeted therapeutic and molecular imaging probe provides a promising paradigm for the development of cancer theranostics.
