title: Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma.
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.
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Mingqian
authors.initials: M
authors.lastname: Feng
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.forename: Ruoqi
authors.initials: R
authors.lastname: Wang
authors.forename: Weizao
authors.initials: W
authors.lastname: Chen
authors.forename: Yan-Gao
authors.initials: YG
authors.lastname: Man
authors.forename: William Douglas
authors.initials: WD
authors.lastname: Figg
authors.forename: Xin Wei
authors.initials: XW
authors.lastname: Wang
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
authors.forename: Mitchell
authors.initials: M
authors.lastname: Ho
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D053673:Glypicans / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009368:Neoplasm Transplantation; D057127:Single-Chain Antibodies / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; C105937:GPC3 protein, human; D053673:Glypicans; D009363:Neoplasm Proteins; D057127:Single-Chain Antibodies