Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma

Mingqian Feng, Wei Gao, Ruoqi Wang, Weizao Chen, Yan Gao Man, William Douglas Figg, Xin Wei Wang, Dimiter S. Dimitrov, Mitchell Ho*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

153 Scopus citations

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.

Original languageEnglish
Pages (from-to)E1083-E1091
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number12
DOIs
StatePublished - 19 Mar 2013
Externally publishedYes

Keywords

  • Cell growth
  • Heparan sulfate proteoglycans
  • Liver cancer
  • Monoclonal antibodies
  • Phage display

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