Mitchell Ho, Ph.D.
Mitchell Ho has pioneered the production of therapeutic antibodies that recognize glypicans in cancer cells. His laboratory studies glypicans as a new family of tumor antigens and makes 'single domain antibodies' that have the ability to bind functional regions in signaling complexes. Several antibody therapeutics, including immunotoxins and chimeric antigen receptor (CAR) T cells, are being developed for the treatment of liver cancer, pancreatic cancer and childhood cancers.
Novel antibody therapeutics targeting glypicans and mesothelin in cancer
Dr. Ho’s laboratory develops new antibody engineering technologies and applies them to advance the development of antibody therapeutics with a focus on glypicans as a new family of tumor antigens. We use 'single domain antibodies' that can reveal novel epitopes unreachable by conventional antibodies and interrupt signaling processes responsible for the development of cancer.
Glypicans are important modulators of signal transduction pathways in development and disease. However, the role of glypicans in cancer pathogenesis is poorly understood. We generated antibodies (HN3 and YP7) that bind glypican-3 (GPC3) on liver cancer cells. HN3 is a unique human single domain antibody that recognizes a cryptic Wnt binding site in the protein core of GPC3. The YP7 antibody binds an epitope close to cell surface. We have engineered chimeric proteins composed of an antibody fragment fused to a bacterial toxin (i.e. an immunotoxin). The HN3-based immunotoxin causes regression of liver cancer in mice via inhibition of cancer signaling (Wnt/Yap) and by blocking protein synthesis. We are also interested in exploring whether other glypicans could be potential tumor targets. We have recently found that GPC2 protein is highly expressed in about half of neuroblastoma cases and that high GPC2 expression correlates with poor overall survival compared with patients with low GPC2 expression. GPC2 silencing inactivates Wnt/β-catenin signaling and reduces the expression of the target gene N-Myc, an oncogenic driver of neuroblastoma tumorigenesis. We have generated human single-domain antibodies (e.g. LH7) specific for GPC2 and found that the antibodies can inhibit Wnt/β-catenin signaling by disrupting the interaction of GPC2 and Wnt3a. Furthermore, we have developed two forms of antibody therapeutics, immunotoxins and chimeric antigen receptor (CAR) T cells. Immunotoxin treatment can inhibit neuroblastoma growth in mice. CAR T cells targeting GPC2 eliminate neuroblastoma in mice, indicating GPC2 is a promising new target in neuroblastoma.
Our lab also focuses on mesothelin because it is expressed in mesothelioma, pancreatic cancer and other cancers. The molecular interaction between mesothelin and MUC16 (also known as CA125) may facilitate the implantation and spread of tumors. We identified the functional domain (named IAB, 296-359) in mesothelin for MUC16. To develop new therapeutic options for mesothelin, we have generated antibodies (HN1 and YP218). HN1 is a human antibody that disrupts the mesothelin-MUC16 interaction. YP218 is a rabbit monoclonal antibody that recognizes a unique site in mesothelin located close to the cell surface. We have developed a general method for humanization of rabbit and mouse monoclonal antibodies. Our new anti-mesothelin antibodies show great potential for the treatment of mesothelioma, pancreatic cancer, ovarian cancer and other solid tumors.
Drug resistance is an important component of tumor biology that requires a complex cellular environment for study. Along with our collaborators, we have established ex vivo tumor spheroid models using cell lines and primary patient cells. This allows us to study the molecular mechanisms of antibody drug resistance in a physiologically-relevant cellular model. We have also used microarrays to profile gene expression in both spheroids and monolayers to identify new targets specific to the 3D biological structure of cancer.
Antibody engineering is typically carried out by displaying antibody fragments on the surface of microorganisms (e.g. phage, bacteria and yeast). We established a new antibody engineering method known as 'mammalian cell display' that is adapted from yeast cell display. Using this approach, antibody fragments are expressed on human HEK-293 cells, and high affinity antigen binders are isolated from a combinatory library via flow cytometry.
BIOC301/302 - Biochemistry I/II
Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma..Proc Natl Acad Sci U S A.. doi: 10.1073/pnas.1706055114., 2017. [ Journal Article ]
Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis.Nat. Commun.. 6: 6536, 2015. [ Journal Article ]
Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therap.Hepatology. 60(2): 576-87, 2014. [ Journal Article ]
Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma.Proc Natl Acad Sci USA . 110(12): E1083-91, 2013. [ Journal Article ]
A human single-domain antibody elicits potent antitumor activity by targeting an epitope in mesothelin close to the cancer cell surface.Mol Cancer Ther. 12(4): 416-26, 2013. [ Journal Article ]
Mitchell Ho is a Senior Investigator at the National Cancer Institute (NCI), NIH. Dr. Ho and his team are designing antibodies to inhibit signaling pathways responsible for the growth of cancer. He has two main research areas. One focuses on decreasing the size of the antibody to make a 'single domain antibody' so it can target a buried functional region in receptors or signaling complexes. The second area is to establish new therapeutic targets with a focus on tumor-specific glypicans and make antibodies that modulate their activity. His group was the first to discover inhibitory antibodies with the unique ability to block Wnt/Yap signaling pathway via binding cryptic functional regions on glypican-3 in liver cancer.
Dr. Ho received a Ph.D. with Mariangela Segre from the University of Illinois at Urbana-Champaign where he won a NIDA/NRSA fellowship to design anti-idiotypic antibodies as cocaine antagonists. He was a postdoctoral fellow with Ira Pastan (NCI) to engineer immunotoxins against cancer. He was recruited to NCI as a tenure track Investigator in 2008 and was promoted as a tenured Senior Investigator in 2015. Dr. Ho is a recipient of the NCI Director's Intramural Innovation Award, the Meso Foundation Award, the OCRFA Individual Investigator Award and the NIH Merit Award. Dr. Ho serves on the Board of Distinguished Advisors for the Antibody Society. He is also the Chair of the Department of Biochemistry for the FAES Graduate School at the NIH.
|Hejiao Bian Ph.D.||Postdoctoral Fellow (CRTA)|
|Zhijian Duan Ph.D.||Postdoctoral Fellow (Visiting)|
|Bryan D. Fleming Ph.D.||Postdoctoral Fellow (CRTA)|
|Ying Fu Ph.D.||Postdoctoral Fellow (CRTA)|
|Jessica Hong||Research Biologist|
|Nan Li Ph.D.||Research Fellow (Visiting)|
|Yaping Sun Ph.D.||Postdoctoral Fellow (Visiting)|
|Yifan Zhang Ph.D.||Postdoctoral Fellow (Visiting)|