Heparan sulfate proteoglycans (HSPGs) regulate numerous cell surface signaling events. They are extracellular modulators of signal transduction pathways during development and disease. However, their role in cancer development is poorly understood. 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. In the recent fiscal years, we have focused on evaluating glypican-3 (GPC3) as a new target in hepatocellular carcinoma (HCC), the most common form of primary liver cancers. To this end, we produced mouse monoclonal antibodies (e.g. YP7) that recognize a C-terminal site (511-560) in GPC3 [Phung et al., MAbs, PMID 22820551, 2012]. In addition, we generated two human monoclonal antibodies (HN3 and HS20) by phage display technology. HN3 is a human heavy-chain antibody that recognizes a novel 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; Gao et al., PLoS One, PMID: 26332121, 2016; Gao et al., Scientific Reports, PMID: 27185050, 2016 ]. Our antibodies exhibit significant inhibition of HCC xenograft tumor growth in mice and show potential for use as therapeutic candidates. Furthermore, 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 immunotoxin caused regression of liver cancer in mice. Interestingly, Its novel 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. To pursue clinical development of our anti-GPC3 immunotoxin for the treatment of liver cancer, in FY16 we generated a new version of the anti-GPC3 immunotoxin (HN3-mPE24) and found that the second generation greatly reduced side effects and had good anti-tumor activity when used at high doses in mice. We summarized the most recent research in the development of anti-GPC3 immunotoxin therapy and published a research article in Oncotarget [Wang et al., PMID: 27419635, 2016]. The potency and lack of drug resistance makes the new immunotoxin-based liver cancer therapy very attractive. In addition to the immunotoxin therapy, along with our collaborators, we used our anti-GPC3 antibodies to construct various clinical formats for targeted therapy of liver cancer including photoimmunotherapy and published our collaborative research in two research articles [Hanaoka et al. Mol Pharm, 2015; Hanaoka et al. Nanomedicine, 2015]. In addition to targeted therapies, our antibodies have been widely used as a research tool to analyze the role of HSPGs in Wnt signaling and other important biological processes. We have identified the Wnt binding domain in heparan sulfate using our HS20 human antibody in collaboration with Dr. Jian Liu's lab in the University of North Carolina and published a research article in FY16 [Gao et al., Scientific Reports, PMID: 27185050, 2016]. In the mesothelin project, we have collaborated with Dr. Ira Pastan's lab and 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) for the treatment of mesothelioma and other mesothelin-positive cancers [Zhang et al., Scientific Reports, PMID: 25996440, 2015].
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