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Therapeutic potential of targeting glypican-3 in hepatocellular carcinoma.

ABSTRACT: Glypican-3 (GPC3) is a developmentally-regulated oncofetal protein that has been established as a clinically-relevant biomarker for early hepatocellular carcinoma (HCC). It is one of the first transcripts to appear during malignant hepatocyte transformation, and is expressed at the protein level in approximately half of high-grade dysplastic macronodules in cirrhotic liver. Several studies show it is expressed in most (75 to 100%) of HCCs confirmed by histopathology. The protein is anchored to the hepatocyte membrane by a glycosyl-phosphatidylinositol (GPI) anchor and shows consistent membrane immunostaining pattern, making it a viable target for immunotherapeutic approaches. Targeting GPC3 for therapeutic intervention is a promising approach for the clinical management of HCC and selected other tumors that express the marker.

SUBMITTER: Allegretta M

PROVIDER: S-EPMC3843004 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Therapeutic potential of targeting glypican-3 in hepatocellular carcinoma.

Allegretta Mark M Filmus Jorge J

Anti-cancer agents in medicinal chemistry 20110701 6

Glypican-3 (GPC3) is a developmentally-regulated oncofetal protein that has been established as a clinically-relevant biomarker for early hepatocellular carcinoma (HCC). It is one of the first transcripts to appear during malignant hepatocyte transformation, and is expressed at the protein level in approximately half of high-grade dysplastic macronodules in cirrhotic liver. Several studies show it is expressed in most (75 to 100%) of HCCs confirmed by histopathology. The protein is anchored to t ...[more]

PMID: 21554204

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Project description:UnlabelledHepatocellular carcinoma (HCC) is an increasingly lethal malignancy for which management is critically dependent on accurate imaging. Glypican-3 (GPC3) is a cell surface receptor overexpressed in most HCCs and provides a unique target for molecular diagnostics. The use of monoclonal antibodies (mAbs) that target GPC3 (αGPC3) in PET imaging has shown promise but comes with inherent limitations associated with mAbs such as long circulation times. This study used (89)Zr-conjugated F(ab')2 fragments directed against GPC3 ((89)Zr-αGPC3-F(ab')2) to evaluate the feasibility of the fragments as a diagnostic immuno-PET imaging probe.MethodsImmobilized ficin was used to digest αGPC3, creating αGPC3-F(ab')2 fragments subsequently conjugated to (89)Zr. In vivo biodistribution and PET studies were performed on GPC3-expressing HepG2 and GPC3-nonexpressing RH7777 orthotopic xenografts.ResultsReliable αGPC3-F(ab')2 production via immobilized ficin digestion was verified by high-performance liquid chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis. (89)Zr-αGPC3-F(ab')2 demonstrated F(ab')2-dependent, antigen-specific cell binding. HepG2 tumor uptake was higher than any other tissue, peaking at 100 ± 21 percentage injected dose per gram (%ID/g) 24 h after injection, a value 33- to 38-fold higher than GPC3-nonexpressing RH7777 tumors. The blood half-life of the (89)Zr-αGPC3-F(ab')2 conjugate was approximately 11 h, compared with approximately 115 h for historic mAb controls. This shorter half-life enabled clear tumor visualization on PET 4 h after administration, with a resultant peak tumor-to-liver contrast ratio of 23.3. Blocking antigen-expressing tumors with an excess of nonradiolabeled αGPC3 resulted in decreased tumor uptake similar to native liver. The kidneys exhibited high tissue uptake, peaking at 24 h with 83 ± 12 %ID/g. HepG2 tumors ranging from 1.5 to 7 mm were clearly visible on PET, whereas larger RH7777 tumors displayed signal lower than background liver tissue.ConclusionThis study demonstrates the feasibility of using (89)Zr-αGPC3-F(ab')2 for intrahepatic tumor localization with small-animal PET. Faster blood clearance and lower background liver uptake enable excellent signal-to-noise ratios at early time points. Increased renal uptake is similar to that as has been seen with clinical radioactive peptide imaging. (89)Zr-αGPC3-F(ab')2 addresses some of the shortcomings of whole-antibody immuno-PET probes. Further optimization is warranted to maximize probe sensitivity and specificity in the process of clinical translation.

Dataset Information

Therapeutic potential of targeting glypican-3 in hepatocellular carcinoma.

Publications

Therapeutic potential of targeting glypican-3 in hepatocellular carcinoma.

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