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.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- March 2013
- DOI:
- 10.1073/pnas.1217868110
- Bibcode:
- 2013PNAS..110E1083F