Liver cancer is the fifth most common cancer and the third leading cause of cancer mortality in the world. Hepatocelluar carcinoma (HCC) accounts for approximately 75% of liver cancer cases, while intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumor. There is an urgent need to develop new drugs for the treatment of liver cancer. Project 1: Targeting GPC3 in HCC and other cancers GPC3 is a heparan sulfate proteoglycan highly expressed in HCC and holds potential for liver cancer therapy. The biological functions of GPC3 and its role in liver tumorigenesis remain elusive. Our work helps uncover the role of GPC3 in liver cancer cell growth. We produced and analyzed a recombinant soluble GPC3 (25-559) that inhibited the growth of HCC cells and presumed to compete with endogenous glypican-3 for binding to growth factors on the cancer cell surface. Our lab isolated a panel of mouse monoclonal antibodies including YP7 that recognize the C-terminal end (511-560) of GPC3. YP7 binds GPC3 with high affinity for HCC. It is highly sensitive in that it also detects GPC3 in low expression ovarian clear cell carcinoma and melanoma cells. In FY13, the GPC3 mouse monoclonal antibody work was reported in the journal MAbs (PMID: 22820551). Recently, we generated a human single-domain antibody, HN3, with high affinity for cell-surface-associated GPC3 molecules. The human antibody recognizes a unique conformational epitope in the core protein of GPC3. HN3 inhibits proliferation of HCC cells and exhibits significant inhibition of HCC xenograft tumor growth in mice. The underlying mechanism of HN3 action may involve cell-cycle arrest at G1 phase through Yes-associated protein (YAP) signaling, suggesting a novel mechanism for GPC3-targeted cancer therapy. In FY13, the HN3 antibody research was published in Proc Natl Acad Sci USA (PMID: 23471984). Project 2: Targeting mesothelin in ICC and other cancers Mesothelin is expressed at high levels in ICC, mesothelioma, ovarian cancer, and other cancers. The interaction between mesothelin and MUC16 (also known as CA125) may facilitate the implantation and spread of tumors. We experimentally established the 64-amino acid functional binding domain (IAB, 296-359) in the N-terminus of cell surface mesothelin for MUC16. HN125, an immunoadhesin that consists of the IAB domain and the Fc portion of a human antibody, disrupts the cancer cell adhesion mediated by the MUC16-mesothelin interaction, and elicits antibody-dependent cell mediated cytotoxicity against MUC16-positive tumor cells. Subsequently, we generated the HN1 and SD1 human monoclonal antibodies. HN1 binds the N-terminal end of cell surface mesothelin, disrupts the mesothelin-MUC16 interaction and elicits antibody-dependent cell mediated cytotoxicity against tumor cells. SD1 is a human single-domain antibody that recognizes the C-terminal end (539-588) of mesothelin close to the cell surface and exhibits complement-dependent cytotoxicity against tumor cells. In FY13, the SD1 human antibody to mesothelin was reported in Mol Cancer Ther (PMID: 23371858). The new human antibodies show potential for use as cancer therapeutic candidates.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Cancer Institute Division of Basic Sciences
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Zhang, Yi-Fan; Ho, Mitchell (2016) Humanization of high-affinity antibodies targeting glypican-3 in hepatocellular carcinoma. Sci Rep 6:33878
Nagaya, Tadanobu; Nakamura, Yuko; Sato, Kazuhide et al. (2016) Near infrared photoimmunotherapy with an anti-mesothelin antibody. Oncotarget 7:23361-9
Wang, Chunguang; Gao, Wei; Feng, Mingqian et al. (2016) Construction of an immunotoxin, HN3-mPE24, targeting glypican-3 for liver cancer therapy. Oncotarget :
Fleming, Bryan D; Ho, Mitchell (2016) Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer. Toxins (Basel) 8:
Gao, Wei; Xu, Yongmei; Liu, Jian et al. (2016) Epitope mapping by a Wnt-blocking antibody: evidence of the Wnt binding domain in heparan sulfate. Sci Rep 6:26245
Zhang, Yi-Fan; Phung, Yen; Gao, Wei et al. (2015) New high affinity monoclonal antibodies recognize non-overlapping epitopes on mesothelin for monitoring and treating mesothelioma. Sci Rep 5:9928
Gao, Wei; Kim, Heungnam; Ho, Mitchell (2015) Human Monoclonal Antibody Targeting the Heparan Sulfate Chains of Glypican-3 Inhibits HGF-Mediated Migration and Motility of Hepatocellular Carcinoma Cells. PLoS One 10:e0137664
Gao, Wei; Tang, Zhewei; Zhang, Yi-Fan et al. (2015) Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis. Nat Commun 6:6536
Gao, Wei; Kim, Heungnam; Feng, Mingqian et al. (2014) Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy. Hepatology 60:576-87
Kim, Heungnam; Gao, Wei; Ho, Mitchell (2013) Novel immunocytokine IL12-SS1 (Fv) inhibits mesothelioma tumor growth in nude mice. PLoS One 8:e81919

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