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Mitchell Ho, Ph.D.

Portait Photo of Mitchell Ho
Laboratory of Molecular Biology
Head, Antibody Therapy Section
Investigator
Center for Cancer Research
National Cancer Institute
Building 37, Room 5002C
Bethesda, MD 20892-4264
Phone:  
301-451-8727
Fax:  
301-480-4667
E-Mail:  
homi@mail.nih.gov

Biography

Dr. Ho received his Ph.D. in Immunology from the University of Illinois at Urbana-Champaign under Mariangela Segre. He won a National Research Service Award Predoctoral Fellowship from NIDA for his Ph.D. thesis research on the generation of monoclonal antibodies against cocaine addiction. He was a postdoctoral fellow under Ira Pastan at NCI and generated immunotoxins against cancer. He also conducted research at PDL BioPharma and DNAX (now Merck Research Labs), where he developed an interest in phage display antibody engineering and high-throughput flow cytometry technologies. Dr. Ho is a recipient of the NCI Director's Intramural Innovation Award for Principal Investigators, the Mesothelioma Applied Research Foundation Grant Award, and the Ovarian Cancer Research Fund Individual Investigator Award. He is Chair of the NIH Antibody Interest Group, and he is on the Antibody Society's Board of Distinguished Advisors. He has served on the editorial boards of peer-reviewed journals and has also served on grant review panels for NIH, FDA and DOD as well as cancer foundations. Dr. Ho regularly presents at international symposia and is a member of the organizing committees for several international conferences on therapeutic antibodies. He is an honorary Zijiang Lecture Professor of East China Normal University and a faculty member in the Department of Biochemistry and Biophysics in the FAES Graduate School at the NIH.

Research

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).

Teaching Interests
BIOC301/302 - Biochemistry I/II

This page was last updated on 7/1/2014.