Mitchell Ho, Ph.D.
Laboratory of Molecular Biology
Building 37, Room 5002
Bethesda, MD 20892-4264
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
Mitchell Ho is a Senior Investigator at the National Cancer Institute, NIH. He received his Ph.D. from the University of Illinois at Urbana-Champaign. He was tenured at NIH in 2015. Antibody-based therapeutics is a major component in the cancer treatment landscape. However, for many cancers we know little about what tumor antigens can be safely and effectively targeted to discriminate cancers from normal tissues. Dr. Ho studies heparan sulfate proteoglycans including GPC2 and GPC3 as potential co-receptors for Wnt signaling molecules and as new targets for cancer therapy. His research also demonstrates that ‘single domain antibodies’ can modulate biological processes important for cancer development by binding protein clefts in signaling complexes. By targeting tumor specific shared antigens, his laboratory has developed immunotoxins and CAR T cells for treating liver cancer, childhood cancers and other cancers. Dr. Ho has received many honors including the APAO Scientific Achievement Award. He is the Editor-In-Chief for the international journal ‘Antibody Therapeutics’ and the Chair of the Department of Biochemistry for the FAES Graduate School at the NIH.
Wang C, Gao W, Feng M, Pastan I, Ho M. Construction of an immunotoxin, HN3-mPE24, targeting glypican-3 for liver cancer therapy. Oncotarget. 2017;8(20):32450-32460.
Gao W, Tang Z, Zhang YF, Feng M, Qian M, Dimitrov DS, Ho M. Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis. Nat Commun. 2015;6:6536.
Gao W, Kim H, Feng M, Phung Y, Xavier CP, Rubin JS, Ho M. Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy. Hepatology. 2014;60(2):576-87.
Feng M, Gao W, Wang R, Chen W, Man YG, Figg WD, Wang XW, Dimitrov DS, Ho M. Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2013;110(12):E1083-91.
Tang Z, Feng M, Gao W, Phung Y, Chen W, Chaudhary A, St Croix B, Qian M, Dimitrov DS, Ho M. A human single-domain antibody elicits potent antitumor activity by targeting an epitope in mesothelin close to the cancer cell surface. Mol Cancer Ther. 2013;12(4):416-26.
Related Scientific Focus Areas
Biomedical Engineering and Biophysics
Molecular Biology and Biochemistry
This page was last updated on September 16th, 2020