A novel targeting therapy of malignant mesothelioma using anti-podoplanin antibody

Shinji Abe, Yuki Morita, Mika Kaneko, Masaki Hanibuchi, Yuta Tsujimoto, Hisatsugu Goto, Soji Kakiuchi, Yoshinori Aono, Jun Huang, Seidai Sato, Masatoshi Kishuku, Yuki Taniguchi, Mami Azuma, Kazuyoshi Kawazoe, Yoshitaka Sekido, Seiji Yano, Shin Ichi Akiyama, Saburo Sone, Kazuo Minakuchi, Yukinari KatoYasuhiko Nishioka

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69 Citations (Scopus)

Abstract

Podoplanin (Aggrus), which is a type I transmembrane sialomucin-like glycoprotein, is highly expressed in malignant pleural mesothelioma (MPM). We previously reported the generation of a rat anti-human podoplanin Ab, NZ-1, which inhibited podoplanin-induced platelet aggregation and hematogenous metastasis. In this study, we examined the antitumor effector functions of NZ-1 and NZ-8, a novel rat-human chimeric Ab generated from NZ-1 including Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against MPM in vitro and in vivo. Immunostaining with NZ-1 showed the expression of podoplanin in 73% (11 out of 15) of MPM cell lines and 92% (33 out of 36) of malignant mesothelioma tissues. NZ-1 could induce potent ADCC against podoplanin-positive MPM cells mediated by rat NK (CD161a+) cells, but not murine splenocytes or human mononuclear cells. Treatment with NZ-1 significantly reduced the growth of s.c. established tumors of MPM cells (ACC-MESO-4 or podoplanin-transfected MSTO-211H) in SCID mice, only when NZ-1 was administered with rat NK cells. In in vivo imaging, NZ-1 efficiently accumulated to xenograft of MPM, and its accumulation continued for 3 wk after systemic administration. Furthermore, NZ-8 preferentially recognized podoplanin expressing in MPM, but not in normal tissues. NZ-8 could induce higher ADCC mediated by human NK cells and complement-dependent cytotoxicity as compared with NZ-1. Treatment with NZ-8 and human NK cells significantly inhibited the growth of MPM cells in vivo. These results strongly suggest that targeting therapy to podoplanin with therapeutic Abs (i.e., NZ-8) derived from NZ-1 might be useful as a novel immunotherapy against MPM.

Original languageEnglish
Pages (from-to)6239-6249
Number of pages11
JournalJournal of Immunology
Volume190
Issue number12
DOIs
Publication statusPublished - 2013 Jun 15

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Abe, S., Morita, Y., Kaneko, M., Hanibuchi, M., Tsujimoto, Y., Goto, H., Kakiuchi, S., Aono, Y., Huang, J., Sato, S., Kishuku, M., Taniguchi, Y., Azuma, M., Kawazoe, K., Sekido, Y., Yano, S., Akiyama, S. I., Sone, S., Minakuchi, K., ... Nishioka, Y. (2013). A novel targeting therapy of malignant mesothelioma using anti-podoplanin antibody. Journal of Immunology, 190(12), 6239-6249. https://doi.org/10.4049/jimmunol.1300448