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Hepatology. 2019 Aug;70(2):563-576. doi: 10.1002/hep.30326. Epub 2019 Feb 19.

Glypican-3-Specific Antibody Drug Conjugates Targeting Hepatocellular Carcinoma.

Author information

1
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
2
NCATS Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
3
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD.

Abstract

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in the world. Therapeutic outcomes of HCC remain unsatisfactory, and novel treatments are urgently needed. GPC3 (glypican-3) is an emerging target for HCC, given the findings that 1) GPC3 is highly expressed in more than 70% of HCC; (2) elevated GPC3 expression is linked with poor HCC prognosis; and (3) GPC3-specific therapeutics, including immunotoxin, bispecific antibody and chimeric antigen receptor T cells. have shown promising results. Here, we postulate that GPC3 is a potential target of antibody-drug conjugates (ADCs) for treating liver cancer. To determine the payload for ADCs against liver cancer, we screened three large drug libraries (> 9,000 compounds) against HCC cell lines and found that the most potent drugs are DNA-damaging agents. Duocarmycin SA and pyrrolobenzodiazepine dimer were chosen as the payloads to construct two GPC3-specific ADCs: hYP7-DC and hYP7-PC. Both ADCs showed potency at picomolar concentrations against a panel of GPC3-positive cancer cell lines, but not GPC3 negative cell lines. To improve potency, we investigated the synergetic effect of hYP7-DC with approved drugs. Gemcitabine showed a synergetic effect with hYP7-DC in vitro and in vivo. Furthermore, single treatment of hYP7-PC induced tumor regression in multiple mouse models. Conclusion: We provide an example of an ADC targeting GPC3, suggesting a strategy for liver cancer therapy.

PMID:
30353932
PMCID:
PMC6482108
[Available on 2020-08-01]
DOI:
10.1002/hep.30326

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