title: A novel targeting therapy of malignant mesothelioma using anti-podoplanin antibody.
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.
authors.affiliation: Central Office for Clinical Pharmacy Training, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Abe
authors.forename: Yuki
authors.initials: Y
authors.lastname: Morita
authors.forename: Mika Kato
authors.initials: MK
authors.lastname: Kaneko
authors.forename: Masaki
authors.initials: M
authors.lastname: Hanibuchi
authors.forename: Yuta
authors.initials: Y
authors.lastname: Tsujimoto
authors.forename: Hisatsugu
authors.initials: H
authors.lastname: Goto
authors.forename: Soji
authors.initials: S
authors.lastname: Kakiuchi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Aono
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.forename: Seidai
authors.initials: S
authors.lastname: Sato
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kishuku
authors.forename: Yuki
authors.initials: Y
authors.lastname: Taniguchi
authors.forename: Mami
authors.initials: M
authors.lastname: Azuma
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kawazoe
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Akiyama
authors.forename: Saburo
authors.initials: S
authors.lastname: Sone
authors.forename: Kazuo
authors.initials: K
authors.lastname: Minakuchi
authors.forename: Yukinari
authors.initials: Y
authors.lastname: Kato
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nishioka
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D008654:Mesothelioma / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D010997:Pleural Neoplasms / Q000276:immunology*; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000098853:Podoplanin
chemical_list: D000911:Antibodies, Monoclonal; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; C117468:PDPN protein, human; D000098853:Podoplanin