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A Novel Targeting Therapy of Malignant Mesothelioma Using Anti-Podoplanin Antibody

Shinji Abe, Yuki Morita, Mika Kato 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 Kato and Yasuhiko Nishioka
J Immunol May 20, 2013, 1300448; DOI: https://doi.org/10.4049/jimmunol.1300448
Shinji Abe
*Central Office for Clinical Pharmacy Training, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan;
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Yuki Morita
†Department of Pharmacy, Tokushima University Hospital, Tokushima 770-8503, Japan;
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Mika Kato Kaneko
‡Regional Innovation Strategy Support Program, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
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Masaki Hanibuchi
§Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan;
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Yuta Tsujimoto
‡Regional Innovation Strategy Support Program, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
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Hisatsugu Goto
§Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan;
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Soji Kakiuchi
§Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan;
¶Department of Medical Oncology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan;
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Yoshinori Aono
§Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan;
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Jun Huang
§Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan;
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Seidai Sato
§Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan;
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Masatoshi Kishuku
†Department of Pharmacy, Tokushima University Hospital, Tokushima 770-8503, Japan;
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Yuki Taniguchi
†Department of Pharmacy, Tokushima University Hospital, Tokushima 770-8503, Japan;
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Mami Azuma
*Central Office for Clinical Pharmacy Training, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan;
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Kazuyoshi Kawazoe
†Department of Pharmacy, Tokushima University Hospital, Tokushima 770-8503, Japan;
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Yoshitaka Sekido
‖Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan; and
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Seiji Yano
#Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan
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Shin-ichi Akiyama
¶Department of Medical Oncology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan;
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Saburo Sone
§Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan;
¶Department of Medical Oncology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan;
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Kazuo Minakuchi
†Department of Pharmacy, Tokushima University Hospital, Tokushima 770-8503, Japan;
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Yukinari Kato
‡Regional Innovation Strategy Support Program, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
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Yasuhiko Nishioka
§Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan;
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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.

Footnotes

  • This work was supported in part by Kakenhi (Grants 24390210, 22390166, 23790185, 23701043, and 23791584), a Grant-in-Aid for Scientific Research (B) (to Y.N. and S.S.) and Grants-in-Aid for Young Scientists (B) (to S.A., M.K.K., and Y.K.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Mitsubishi Pharma Research Foundation (to Y.K.), the Children's Cancer Association of Japan (to Y.K.), the Intelligent Cosmos Academic Foundation (to Y.K.), the Platform for Drug Discovery, Informatics, and Structural Life Science (to M.K.K. and Y.K.), and the Regional Innovation Strategy Support Program (to Y.K.).

  • Received February 15, 2013.
  • Accepted March 17, 2013.
  • Copyright © 2013 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 209 (1)
The Journal of Immunology
Vol. 209, Issue 1
1 Jul 2022
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A Novel Targeting Therapy of Malignant Mesothelioma Using Anti-Podoplanin Antibody
Shinji Abe, Yuki Morita, Mika Kato 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 Kato, Yasuhiko Nishioka
The Journal of Immunology May 20, 2013, 1300448; DOI: 10.4049/jimmunol.1300448

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A Novel Targeting Therapy of Malignant Mesothelioma Using Anti-Podoplanin Antibody
Shinji Abe, Yuki Morita, Mika Kato 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 Kato, Yasuhiko Nishioka
The Journal of Immunology May 20, 2013, 1300448; DOI: 10.4049/jimmunol.1300448
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