title: The chimeric antibody chLpMab-7 targeting human podoplanin suppresses pulmonary metastasis via ADCC and CDC rather than via its neutralizing activity.
abstract: Podoplanin (PDPN/Aggrus/T1α) binds to C-type lectin-like receptor-2 (CLEC-2) and induces platelet aggregation. PDPN is associated with malignant progression, tumor metastasis, and poor prognosis in several types of cancer. Although many anti-human PDPN (hPDPN) monoclonal antibodies (mAbs), such as D2-40 and NZ-1, have been established, these epitopes are limited to the platelet aggregation-stimulating (PLAG) domain (amino acids 29-54) of hPDPN. Recently, we developed a novel mouse anti-hPDPN mAb, LpMab-7, which is more sensitive than D2-40 and NZ-1, using the Cancer-specific mAb (CasMab) method. The epitope of LpMab-7 was shown to be entirely different from that of NZ-1, a neutralizing mAb against the PLAG domain according to an inhibition assay and lectin microarray analysis. In the present study, we produced a mouse-human chimeric anti-hPDPN mAb, chLpMab-7. ChLpMab-7 showed high antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Furthermore, chLpMab-7 inhibited the growth of hPDPN-expressing tumors in vivo. Although chLpMab-7 recognizes a non-PLAG domain of hPDPN, it suppressed the hematogenous metastasis of hPDPN-expressing tumors. These results indicated that chLpMab-7 suppressed tumor development and hematogenous metastasis in a neutralization-independent manner. In conclusion, hPDPN shows promise as a target in the development of a novel antibody-based therapy.
authors.affiliation: Department of Regional Innovation, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Yukinari
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kunita
authors.affiliation: Department of Clinical Pharmacy Practice Pedagogy, Institute of Biomedical Sciences, Tokushima University Graduate School, Shou-machi, Tokushima 770-8505, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Abe
authors.affiliation: Department of Regional Innovation, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogasawara
authors.affiliation: Department of Regional Innovation, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fujii
authors.affiliation: Department of Regional Innovation, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Hiroharu
authors.initials: H
authors.lastname: Oki
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, Tokushima University Graduate School, Shou-machi, Tokushima 770-8503, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nishioka
authors.affiliation: Department of Regional Innovation, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Mika K
authors.initials: MK
authors.lastname: Kaneko
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D000939:Epitopes / Q000276:immunology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary* / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D014162:Transfection; D000098853:Podoplanin
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000939:Epitopes; D008562:Membrane Glycoproteins; C117468:PDPN protein, human; D000098853:Podoplanin
keywords: ADCC/CDC; PDPN; metastasis; monoclonal antibody; podoplanin