Abstract B89: The chimeric antibody NZ-12 or CAR T cells targeting human podoplanin possesses antitumor activity against orthotopic xenograft models

Abstract

Abstract Podoplanin (PDPN) is a type I transmembrane mucin-like glycoprotein, which is expressed in lymphatic endothelium. PDPN is also highly expressed in many cancers such as malignant pleural mesothelioma (MPM), lung cancer, and malignant brain tumors including glioblastoma (GBM). We previously developed a rat anti-PDPN monoclonal antibody NZ-1 (rat IgG2a, lambda), and a rat-human chimeric anti-PDPN antibody NZ-8 (human IgG1, kappa), which induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against PDPN-positive cancer cells. Firstly, we demonstrated the antitumor effect of not only NZ-1/NZ-8 but also NZ-12 (human IgG1, lambda), a novel rat-human chimeric anti-PDPN antibody derived from NZ-1, in an MPM orthotopic xenograft SCID mouse model. Treatment with NZ-1 and rat NK (CD161a+) cells inhibited the growth of tumors and the production of pleural effusion in NCI-H290/PDPN or NCI-H226 orthotopic xenograft mouse models. NZ-8 and human NK (CD56+) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Moreover, NZ-12 induced potent ADCC mediated by human MNC, compared with NZ-1/NZ-8. Antitumor effects were observed following treatment with NZ-12 and human NK (CD56+) cells in MPM orthotopic xenograft mice. Secondly, we constructed a lentiviral vector expressing chimeric antigen receptor (CAR) comprising NZ-1-based single chain variable fragment (scFv) with CD28, 4-1BB, and CD3zeta intracellular domains. CAR-transduced peripheral blood monocytes (PBMCs) were immunologically evaluated by calcein-mediated cytotoxic assay, ELISA, tumor size, and overall survival. The generated CAR T cells were specific and effective against PDPN-positive GBM cells in vitro. Systemic injection of the CAR T cells into an immunodeficient mouse model inhibited the growth of intracranial glioma xenografts in vivo. Taken together, PDPN-targeting antibody therapy or PDPN-targeting CAR T cell therapy might provide an efficacious therapeutic strategy for the treatment of MPM or GBM. Citation Format: Yukinari Kato, Satoshi Shiina, Atsushi Natsume, Shinji Abe, Yasuhiko Nishioka, Satoshi Ogasawara, Mika K. Kaneko. The chimeric antibody NZ-12 or CAR T cells targeting human podoplanin possesses antitumor activity against orthotopic xenograft models. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B89.