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Mitchell Ho, Ph.D.
Development of antibody-based cancer therapies
Research in the Ho lab is focused on the application of antibody engineering to the development of cancer therapeutics. In particular, we have generated human and humanized antibodies targeting glypican-3 and mesothelin for the treatment of liver cancer, mesothelioma and other cancers.
Project 1: Targeting glypican-3 in hepatocellular carcinoma
Heparan sulfate proteoglycans (HSPGs) are important modulators of signal transduction pathways during development and disease. They are cell-surface proteins that are modified by the addition of one or several glycosaminoglycan chains. Several HSPGs have been suggested as candidate targets for cancer therapy because of their high expression in certain tumor types. We have generated human and humanized antibodies targeting glypican-3 (GPC3) in hepatocellular carcinoma (HCC). We humanized mouse monoclonal antibodies (e.g. YP7) that recognize a C-terminal site (511-560) in GPC3. Furthermore, we generated two human monoclonal antibodies (HN3 and HS20). HN3 is a human heavy-chain antibody that recognizes a unique conformational epitope in the core protein of GPC3 and inhibits proliferation of HCC cells. The underlying mechanism of HN3 action involves inhibition of Yap signaling in liver cancer cells. HS20 preferentially recognizes the heparan sulfate chains of GPC3. The human antibody disrupts the interaction of Wnt3a and GPC3 and inhibits Wnt/β-catenin signaling. The new antibodies exhibit significant inhibition of HCC xenograft tumor growth in mice and show potential for use as therapeutic candidates.
Project 2: Targeting mesothelin in mesothelioma, ovarian cancer and cholangiocarcinoma
Mesothelin is expressed in mesothelioma, ovarian cancer, pancreatic cancer, lung cancer, gastric cancer, colorectal cancer, breast cancer and cholangiocarcinoma. The molecular interaction between mesothelin and MUC16 (also known as CA125) may facilitate the implantation and spread of tumors. We identified the functional binding domain (named IAB, 296-359) in mesothelin for MUC16. We generated two human monoclonal antibodies specific for mesothelin. The HN1 human antibody disrupts the mesothelin-MUC16 interaction and elicits antibody‐dependent cell-mediated cytotoxicity (ADCC) against tumor cells. SD1 is a human heavy-chain antibody that recognizes a unique site (539-588) in mesothelin close to the cell surface and exhibits complement-dependent cytotoxicity (CDC) as well as ADCC against tumor cells. The new human antibodies show potential for use as cancer therapeutic candidates.
Method 1: Use of tumor spheroids for antibody research
Drug penetration is an important mechanism that requires a complex cellular environment for study. We have used ex vivo tumor spheroids to study the molecular mechanisms of antibody drug resistance with a focus on penetration. We also used microarrays to profile gene expression in spheroids and monolayers and identified genes specific to the 3D biological structure of mesothelioma.
Method 2: Use of mammalian cell display for antibody engineering
Antibody engineering is typically carried out by displaying human antibodies or antibody fragments on the surface of microorganisms (e.g. phage/virus, bacteria and yeast). We established a method known as 'mammalian cell display' that is adapted from Dane Wittrup's (MIT) yeast cell display. Using this approach, functional single-chain antibodies are expressed on human HEK-293 cells, and high affinity antigen binders are isolated from a combinatory library via flow cytometry.
Our collaborators include Dimiter Dimitrov (NCI-Frederick), Xin Wei Wang (NCI), Jeffrey Rubin (NCI), Ira Pastan (NCI), David FitzGerald (NCI), Byungkook Lee (NCI), William Douglas Figg (NCI), Steven Rosenberg (NCI), Raffit Hassan (NCI), Tim Greten (NCI), Hisataka Kobayashi (NCI), Samuel So (Stanford University), Gregory Gores (Mayo Clinic), Lewis Roberts (Mayo Clinic), Shuichi Takayama (University of Michigan), V. Courtney Broaddus (UCSF), Manish Patankar (University of Wisconsin), Christoph Rader (Scripps), Lung-Ji Chang (University of Florida).
BIOC301/302 - Biochemistry I/II
This page was last updated on 7/1/2014.