Development of antibody engineering-based cancer therapies

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Dr. Ho's laboratory conducts research in biochemistry and molecular biology, focusing on glypican biology, antibody engineering, and cancer immunology. With a central interest in cell surface receptor mechanisms, the lab has made important contributions to understanding the biochemical and immunological roles of glypicans, particularly GPC1, GPC2, and GPC3, in cancer development and immunotherapy. They have advanced the field's understanding of glypicans in Wnt and YAP signaling, their structure-function relationships, and discovered novel associated proteins such as FAT1 and AFP. Dr. Ho's team has also developed antibody- and T cell-based immunotherapies for liver cancer, mesothelioma, pediatric cancers, and other malignancies. In addition, the lab creates antibody engineering tools, including mammalian cell surface display and nanobody libraries from sharks and camels, to support drug discovery. Some of their findings have direct clinical relevance. In FY25, Dr. Ho's group published nine peer-reviewed articles. Antibody and cell-based therapies targeting cell surface receptors are emerging as a key class of cancer immunotherapeutics, though viable targets remain limited. The lab has focused on glypican-3 (GPC3), a cell surface proteoglycan and oncofetal antigen. In a study published in Proteoglycan Research, Zhang et al. performed large-scale co-immunoprecipitation (CoIP) and mass spectrometry on liver tumors, identifying 153 GPC3-associated proteins. These were categorized by subcellular localization, with a focus on extracellular candidates. Differential expression and prognostic relevance were assessed using TCGA/GTEx data via GEPIA. Proteins such as IGSF1, AFP, FAT1, FMN1, and GUCY2C were suggested as potential immunotherapy targets. Direct GPC3-AFP interaction was validated through immunoprecipitation and immunofluorescence imaging. This dataset enhances understanding of glypican biology and provides a foundation for target discovery. Glypicans are a family of membrane-bound proteoglycans that regulate key signaling pathways, including Wnt and Hedgehog. They are characterized by a core protein with heparan sulfate chains and a GPI anchor. Aberrant expression of GPC1, GPC2, and GPC3 in cancers disrupts signaling pathways and positions glypicans as emerging immunotherapy targets. However, structural complexes of human glypicans with Wnt and other factors remain unresolved. In a 2025 review, Tsao and Ho examined existing structural data on glypican with a focus on Wnt interactions and discussed implications for cancer therapy development. Cholangiocarcinoma (CCA) is a highly lethal cancer with rising incidence and poor response to conventional treatments. While targeted therapies have benefited select patients, CAR-T cells and personalized vaccines offer new therapeutic possibilities. Dr. Ho's lab, in collaboration with a pediatric oncology group at Johns Hopkins, published a comprehensive overview of antibody-based immunotherapies in CCA. The article discusses strategies for selecting CAR-T and vaccine targets and explores the biology of promising antigens and future directions. In collaboration with the NCI labs, Dr. Ho's team demonstrated that combining a GPC2 CAR with membrane-tethered IL-15/IL-21 enhances anti-tumor efficacy in neuroblastoma (Cancer Immunol Res, 2025). They also reported preclinical results using CAR T cells based on the A101 nanobody targeting mesothelin in immunocompetent mouse models.