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 (K d = 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.heparan sulfate proteoglycans | liver cancer | monoclonal antibodies | phage display | cell growth

Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma

“…A combinational engineered human V H singledomain phage display library, with an estimated size of 2.5 × 10 10 , was used for the screening and has been previously described (56). The phage library was subjected to four rounds of panning on Nunc 96-well Maxisorp plate (Thermo Scientific) as described previously (57)(58)(59). Details are provided in the SI Appendix, SI Materials and Methods.…”

Pharmaceutical properties of supramolecular assembly of co-loaded cardanol/triazole-halloysite systems

“…Liver cancer is a major malignant tumor worldwide and is the third most common cause of cancer-related mortality (Feng et al, 2013). Over 80% of liver cancer patients are diagnosed with hepatocellular carcinoma, which is resistant to most conventional chemotherapeutic agents (Wilson et al, 2012).…”

Development of T Cells Redirected to Glypican-3 for the Treatment of Hepatocellular Carcinoma

“…Multiple studies have demonstrated that GPC3 is an attractive liver cancer-specific target because it is highly expressed in HCC but limited expressed in normal tissues (7). Currently, GPC3-targeted immunotherapeutic strategies utilizing antibodies or a peptide vaccine have been explored for HCC treatment (8)(9)(10)(11)(12). The clinical data of the monoclonal antibody GC33 indicated that it was well tolerated in advanced HCC, suggesting that GPC3 is a relatively safe target.…”