Heparan sulfate proteoglycans (HSPGs) regulate numerous cell surface signaling events. They are extracellular modulators of signal transduction pathways during development and disease. HSPGs are cell-surface proteins that mainly consist of glycosylphosphatidylinositol (GPI)-anchored glypicans and transmembrane syndecans. Several HSPGs are currently being evaluated as potential targets for cancer therapy because of their relatively high expression in certain tumor types. We have generated monoclonal antibodies targeting glypican-3 (GPC3) in hepatocellular carcinoma (HCC), the most common form of primary liver cancers. We generated mouse monoclonal antibodies (e.g. YP7) that recognize a C-terminal site (511-560) in GPC3 [Phung et al., MAbs, PMID 22820551, 2012]. Furthermore, we generated two human monoclonal antibodies (HN3 and HS20). HN3 is a human heavy-chain antibody that recognizes a unique functional site in the core protein of GPC3 and inhibits proliferation of HCC cells. The underlying mechanism of HN3 action involves inhibition of Wnt and Yap signaling in liver cancer cells [Feng et al., PNAS, PMID: 23471984, 2013; Gao et al., Nature Communications, PMID: 25758784, 2015]. HS20 recognizes the heparan sulfate chains of GPC3. The human antibody disrupts the interaction of Wnt3a and GPC3 and inhibits Wnt/beta-catenin signaling [Gao et al., Hepatology, PMID: 24492943, 2014]. Our antibodies exhibit significant inhibition of HCC xenograft tumor growth in mice and show potential for use as therapeutic candidates. In FY15, we found that GPC3 was efficiently internalized from the cell surface and that the HN3-PE38 immunotoxin brought the toxin into the cell, resulting in inhibition of protein synthesis. The HN3-PE38 immunotoxin caused regression of liver cancer in mice. Its mechanism involved both inhibition of cancer signaling (Wnt/Yap) and reduction in protein synthesis. Our strategy combining both antibody and toxin functions could be applicable generally to other immunotoxins and antibody-toxin/drug conjugates. The clinical development of GPC3-targeted immunotoxin therapy for liver cancer is the top priority in our GPC3 project. We summarized our work on the development of anti-GPC3 immunotoxins and published a research article in Nature Communications [Gao et al., PMID: 25758784, 2015]. In the mesothelin project, we have collaborated with Ira Pastan's group. We used rabbit monoclonal antibody technology to identify a panel of interesting antibodies that bind poorly immunogenic sites in mesothelin. We have humanized one of the best candidates (YP218). In FY15, we summarized the development of rabbit monoclonal antibodies to mesothelin and published a research article [Zhang et al., Scientific Reports, PMID: 25996440, 2015].
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