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Recently, research has been conducted with chimeric antigen receptor (CAR)‐T cells to improve efficacy against solid tumors. Humanized CAR improved the long‐term survival of CAR‐T cells in patients' peripheral blood, resulting in increased therapeutic efficacy. Therefore, the humanization of the CAR‐gene sequence is considered an effective method. Podoplanin (PDPN) is a glycosylated transmembrane protein that is highly expressed in solid tumors and is associated with poor prognosis in patients with cancer. Therefore, PDPN is considered a biomarker and good target for cancer treatment with CAR‐T cells. Previously, an anti‐PDPN CAR was generated from a conventional nonhumanized antibody—NZ‐1, the only anti‐PDPN antibody for which a CAR was produced. In this study, we investigated other anti‐PDPN CARs from the antibody NZ‐27, or humanized NZ‐1, to enhance the therapeutic potential of CAR‐T cells. The CAR signal intensity was enhanced by the efficient expression of CAR proteins on the T‐cell surface of NZ‐27 CAR‐T cells, which show tumor‐specific cytotoxicity, proinflammatory cytokine production, and anti‐tumor activity against PDPN‐expressing tumor xenografts in mice that were significantly better than those in nonhumanized NZ‐1 CAR‐T cells.

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