Therapeutically targeting glypican 3 via a conformation specific single domain antibody in hepatocellular carcinoma
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.
Proceedings of the National Academy of Sciences