Our Science – Ho Website

Mitchell Ho, Ph.D.

Laboratory of Molecular Biology Head, Antibody Therapy Unit Investigator National Cancer Institute Building 37, Room 5002C 37 Convent Drive, MSC 4264 Bethesda, MD 20892-4264 Phone:   301-451-8727 Fax:   301-480-4667 E-Mail:   homi@mail.nih.gov

Biography

Dr. Ho obtained his Ph.D. in Immunology from the University of Illinois at Urbana-Champaign. As a National Research Service Award predoctoral fellow, he studied monoclonal antibodies for the treatment of cocaine addiction with Dr. Mariangela Segre. He received his postdoctoral research training in immunotoxin-based therapy of cancer with Dr. Ira Pastan at the NIH. Dr. Ho was recruited to the National Cancer Institute in 2008 as a principal investigator to form the Antibody Therapy Section in the Laboratory of Molecular Biology. He is a recipient of the Mesothelioma Applied Research Foundation Award and the Ovarian Cancer Research Fund Individual Investigator Award. He is a faculty member in the Department of Biochemistry and Biophysics in the FAES Graduate School at NIH since 2005.

Research

Antibody-Based Treatment of Cancer

Research in my laboratory is aimed at understanding the molecular mechanisms underlying cancer in order to develop novel anti-cancer antibody therapies. Our efforts focus on building new therapeutic antibodies directed against ovarian cancer, mesothelioma, and liver cancer.

Mesothelin is overexpressed in a variety of cancers including mesothelioma and ovarian cancer. We have recently discovered that mesothelin is a promising new therapeutic target for non-small cell lung cancer. We have identified and characterized soluble mesothelin proteins shed from cancer cells, which may then be used as a new diagnostic biomarker for cancer. In this way, we have also established a sensitive ELISA-based assay to examine the anti-mesothelin antibody response in ovarian cancer and mesothelioma patients. We have found that antibodies specific for mesothelin are elevated in cancer patients, and that this elevation is associated with high expression of mesothelin in tumors. We continue to study the antibody response against mesothelin in correlation to clinical outcome. Ovarian cancer and malignant mesothelioma frequently express both mesothelin and CA125 (also known as MUC16) at high levels on the cell surface. The interaction between mesothelin and CA125 may facilitate the implantation and peritoneal spread of tumors by cell adhesion. However, the detailed nature of this molecular interaction is unclear and studies of the molecular interaction between mesothelin and CA125 are essential to understanding and eventually controlling peritoneal tumor metastasis. Recent studies done in my laboratory have identified a conformation-sensitive binding domain on mesothelin for CA125. We have also demonstrated that a single chain monoclonal antibody recognizes this CA125-binding domain and blocks the mesothelin-CA125 interaction on cancer cells. The identified CA125-binding domain significantly inhibits cancer cell adhesion and merits evaluation as a new therapeutic agent for preventing or treating peritoneal malignant tumors.

While the mouse is the most common source of monoclonal antibodies against human proteins, it is not always possible to raise high affinity antibodies against those antigens that are highly conserved between human and mouse. Such antigens have little or no immunogenicity in mice due to an immune tolerance. Consequently, the use of a large naive or synthetic human antibody library offers an alternative method for bypassing immunization of mice. In general, antibody engineering is typically carried out by displaying human antibodies or antibody fragments on the surface of microorganisms (e.g. phage, bacteria and yeast). Recently, we have developed a new method known as 'mammalian cell display' that may lead to novel applications involving therapeutic antibody discovery. Using this approach, functional single-chain antibody variable fragments (scFvs) are expressed on human HEK-293 cells and high affinity antigen binders are identified and isolated from a combinatory library via flow cytometry. We are currently assessing mammalian cell display for its potential benefits involving therapeutic antibody discovery and engineering.

Collaborators on these projects include Ira Pastan, NIH; David FitzGerald, NIH; Raffit Hassan, NIH; Christoph Rader, NIH; Byungkook Lee, NIH; Dimiter Dimitrov, NIH; Steven Albelda, University of Pennsylvania; Shuichi Takayama, University of Michigan; Itai Benhar, Tel Aviv University, Israel; Min Qian, East China Normal University Institute of Biomedical Sciences, China.

Teaching Interests
BIOC301/302 - Biochemistry I/II

This page was last updated on 9/28/2009.