Abstract
Glypican-3 (GPC3) has emerged as a candidate therapeutic target in hepatocellular carcinoma (HCC), but the oncogenic role of GPC3 in HCC is poorly understood. Here, we report a human heavy-chain variable domain antibody, HN3, with high affinity (Kd = 0.6 nM) for cell-surface-associated GPC3 molecules. The human antibody recognized a conformational epitope that requires both the amino and carboxy terminal domains of GPC3. HN3 inhibited proliferation of GPC3-positive cells and exhibited significant inhibition of HCC xenograft tumor growth in nude mice. The underlying mechanism of HN3 action may involve cell-cycle arrest at G1 phase through Yes-associated protein signaling. This study suggests a previously unrecognized mechanism for GPC3-targeted cancer therapy.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Antibodies, Neoplasm / pharmacology*
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Antineoplastic Agents / pharmacology*
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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G1 Phase Cell Cycle Checkpoints / drug effects
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Glypicans / antagonists & inhibitors*
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Glypicans / metabolism
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Humans
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Mice
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Mice, Nude
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / metabolism
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Neoplasm Transplantation
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Single-Chain Antibodies / pharmacology*
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Transplantation, Heterologous
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Xenograft Model Antitumor Assays / methods
Substances
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Antibodies, Neoplasm
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Antineoplastic Agents
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GPC3 protein, human
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Glypicans
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Neoplasm Proteins
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Single-Chain Antibodies