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

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 meta...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2013-06, Vol.190 (12), p.6239-6249
Main Authors: Abe, Shinji, Morita, Yuki, Kaneko, Mika Kato, Hanibuchi, Masaki, Tsujimoto, Yuta, Goto, Hisatsugu, Kakiuchi, Soji, Aono, Yoshinori, Huang, Jun, Sato, Seidai, Kishuku, Masatoshi, Taniguchi, Yuki, Azuma, Mami, Kawazoe, Kazuyoshi, Sekido, Yoshitaka, Yano, Seiji, Akiyama, Shin-ichi, Sone, Saburo, Minakuchi, Kazuo, Kato, Yukinari, Nishioka, Yasuhiko
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - immunology
Antibodies, Monoclonal - pharmacology
Flow Cytometry
Humans
Immunohistochemistry
Immunotherapy - methods
Male
Membrane Glycoproteins - immunology
Mesothelioma - immunology
Mice
Mice, SCID
Pleural Neoplasms - immunology
Rats
Rats, Wistar
Recombinant Fusion Proteins - immunology
Recombinant Fusion Proteins - pharmacology
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1300448