The Antibody Therapy Section aims to develop novel antibody therapies for liver cancer as well as other cancers. Project 1: Targeting glypican-3 in hepatocellular carcinoma Liver cancer is the fifth most common cancer and the third leading cause of cancer mortality in the world. Hepatocellular carcinoma (HCC) accounts for approximately 75% of liver cancer cases. Cholangiocarcinoma (CCA) is the second most common primary liver tumor. There is an urgent need for new treatments that can be successfully applied to a large population of liver cancer patients. With a primary interest in investigating glypican-3 (GPC3), this target holds potential for liver cancer therapy, given its high protein expression in HCC. In FY11-12, we generated the YP7 monoclonal antibody (mAb) with high affinity to GPC3 by hybridoma technology. In FY12, we conducted animal testing and showed that YP7 exhibited significant HCC xenograft tumor growth inhibition in mice. This work was published in the journal mAbs and featured on its cover. Ongoing studies are focused on exploring the mechanisms underlying the role of GPC3 in HCC pathogenesis and on the development of human antibodies targeting GPC3 for liver cancer therapy. The NCI has filed patent applications based on our GPC3 monoclonal antibodies. We hope to find industrial partners to collaborate with us in the development of novel GPC3-targeted antibody therapy to treat liver cancer. In FY12, the GPC3 project yielded three publications in the journals mAbs, BioDrugs and Cancer Reports. We presented our work at international symposia such as 2nd Annual PEGS Antibodies for Cancer Therapy Symposium, Protein Discovery &Therapeutics, and Antibodies for the 21st. Project 2: Targeting mesothelin in liver cancer, mesothelioma and ovarian cancer Mesothelin is expressed at high levels in mesothelioma, cholangiocarcinoma, ovarian as well as pancreatic and lung cancers. In FY10, we analyzed protein expression of mesothelin in liver cancer tissues and hypothesized that mesothelin is a potential therapeutic target in cholangiocarcinoma (CCA). In collaboration with Ira Pastan at the NCI, we applied our expertise in phage display technology to identify HN1, a human mAb specific for mesothelin. The HN1 mAb binds cell surface-associated mesothelin with high affinity and kills cancer cells with excellent antibody-dependent cell mediated cytotoxicity (ADCC) and is promising for the treatment of mesothelin-expressing cancers. In FY11, we published the HN1 work in the International Journal of Cancer. Our mesothelin project was supported in part by a Mesothelioma Applied Research Foundation research grant and the Ovarian Cancer Research Fund Individual Investigator Award to Mitchell Ho. In FY12, in collaboration with Ira Pastan and Dimiter Dimitrov (NCI's Frederick National Lab), we isolated novel single-domain human antibodies against mesothelin by phage display technology. These human antibodies may have novel anti-tumor activities against mesothelin-positive tumor cells. The NCI has filed patent applications on our mesothelin antibodies for cancer therapy. NCI also provides the LMB-H226-GL mesothelioma model developed in our lab as a Research Tool to the scientific community. Project 3: Establish in vitro tumor spheroids to investigate antibody therapy. Most studies of anticancer drugs consider only genetic and/or cellular mechanisms at the level of the single cell. However, drug penetration is a highly important additional mechanism and requires a more complex cellular environment for study. In FY11-12, in collaboration with V. Courtney Broaddus (University of California San Francisco) and Shuichi Takayama (University of Michigan), we established in vitro tumor spheroids to study monoclonal antibody therapy. These tumor spheroids may prove invaluable for identifying potential therapeutic targets in addition to providing an innovative platform for screening more effective anti-tumor antibodies. In FY12, we compared the gene expression profiles of 3D spheroids and conventional 2D monolayers using microarray analysis and identified over 100 genes specific to the 3D biological structure of mesothelioma. Some of these genes may have potential as therapeutic targets and diagnostic biomarkers. In FY11-12, this work yielded two research articles in PloS ONE and presented at international symposia such as the Protein Therapeutics Forum and PEGS Antibodies for Cancer Therapy Symposium. The spheroid work was supported in part by the NCI Director's Intramural Innovation Award (Principal Investigator Award) to Mitchell Ho.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010891-05
Application #
8552882
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2012
Total Cost
$735,484
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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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