Integrated Imaging Probe and Bispecific Antibody Development Enables In Vivo Targeting of Glypican-3-Expressing Hepatocellular Carcinoma.

Autor:	Habibollahi P; Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.; Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Gurevich A; Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania., Hui JZ; Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.; Center for Targeted Therapeutics and Translational Nanomedicine, University of Pennsylvania, Philadelphia, Pennsylvania., Weinfurtner K; Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania., McClung G; Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania., Adler J; Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania., Soulen MC; Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania., Kaplan DE; Department of Gastroenterology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania., Nadolski GJ; Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania., Hunt SJ; Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania., Tsourkas A; Center for Targeted Therapeutics and Translational Nanomedicine, University of Pennsylvania, Philadelphia, Pennsylvania.; Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania., Gade TP; Penn Image-Guided Interventions Laboratory, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.; Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2024 Dec 03; Vol. 23 (12), pp. 1815-1826.
DOI:	10.1158/1535-7163.MCT-23-0470
Abstrakt:	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. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu