Assistant Professor University of Tsukuba Nagareyama, Chiba, Japan
Abstract: Chimeric Antigen Receptor (CAR) T-cell therapy has achieved remarkable success in treating CD19-positive B-cell malignancies but faces significant challenges in addressing solid tumors such as antigen specificity and safety concerns regarding off-target effects. Podocalyxin (PODXL), a transmembrane protein linked to tumor progression and poor prognosis in various cancers, represents a promising but difficult therapeutic target because of its expression in normal tissues. To address these challenges, we employed CasMab technology to develop CAR-T cells utilizing the cancer-specific monoclonal antibody PcMab-6, which selectively recognizes cancer-specific modifications on PODXL-expressing cancer cells. Compared to control CAR-T cells derived from a non-cancer-specific antibody (PcMab-47), PcMab-6 CAR-T cells demonstrated significant antitumor activity in vitro with reduced off-target effects. Furthermore, the humanization of PcMab-6 scFv enhanced the persistence and therapeutic efficacy of CAR-T cells, resulting in extended antitumor effects in vivo. These advancements highlight the potential of humanized PODXL-targeted CAR-T cells to provide safer and more effective treatments for solid tumors, paving the way for clinical application.
