Antitumor effect of novel anti-podoplanin antibody NZ-12 against malignant pleural mesothelioma in an orthotopic xenograft model.
Podoplanin (aggrus) is highly expressed in several types of cancers, including malignant pleural mesothelioma (MPM). Previously, we developed a rat anti-human podoplanin mAb, NZ-1, and a rat-human chimeric anti-human podoplanin antibody, NZ-8, derived from NZ-1, which induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against podoplanin-positive MPM cell lines. In this study, we showed the antitumor effect of NZ-1, NZ-8, and NZ-12, a novel rat-human chimeric anti-human podoplanin 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 natural killer (NK) (CD56(+) ) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Furthermore, NZ-12 induced potent ADCC mediated by human MNC, compared with either NZ-1 or NZ-8. Antitumor effects were observed following treatment with NZ-12 and human NK (CD56(+) ) cells in MPM orthotopic xenograft mice. In addition, combined immunotherapy using the ADCC activity of NZ-12 mediated by human NK (CD56(+) ) cells with pemetrexed, led to enhanced antitumor effects in MPM orthotopic xenograft mice. These results strongly suggest that combination therapy with podoplanin-targeting immunotherapy using both NZ-12 and pemetrexed might provide an efficacious therapeutic strategy for the treatment of MPM.
Department of Clinical Pharmacy Practice Pedagogy, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.|Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Shinji
S
Abe
Department of Regional Innovation, Tohoku University Graduate School of Medicine, Sendai, Japan.
Mika Kato
MK
Kaneko
Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Yuki
Y
Tsuchihashi
Department of Clinical Pharmacy Practice Pedagogy, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Toshihiro
T
Izumi
Department of Regional Innovation, Tohoku University Graduate School of Medicine, Sendai, Japan.
Satoshi
S
Ogasawara
Department of Clinical Pharmacy Practice Pedagogy, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Naoto
N
Okada
Department of Clinical Pharmacy Practice Pedagogy, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Chiemi
C
Sato
Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Makoto
M
Tobiume
Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Kenji
K
Otsuka
Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Licht
L
Miyamoto
Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Koichiro
K
Tsuchiya
Department of Clinical Pharmacy Practice Pedagogy, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Kazuyoshi
K
Kawazoe
Department of Regional Innovation, Tohoku University Graduate School of Medicine, Sendai, Japan.
Yukinari
Y
Kato
Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. yasuhiko@tokushima-u.ac.jp.
Yasuhiko
Y
Nishioka
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003165:Complement System Proteins / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D008654:Mesothelioma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D000068437:Pemetrexed / Q000494:pharmacology; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D023041:Xenograft Model Antitumor Assays; D000098853:Podoplanin
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D003165:Complement System Proteins; D008562:Membrane Glycoproteins; D000068437:Pemetrexed; C117468:PDPN protein, human; D000098853:Podoplanin
NZ-12; antibody-dependent cellular cytotoxicity; mesothelioma; orthotopic xenograft model; podoplanin