The chimeric antibody chLpMab-7 targeting human podoplanin suppresses pulmonary metastasis via ADCC and CDC rather than via its neutralizing activity.
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.
['Kato|Yukinari|Y|', 'Kunita|Akiko|A|', 'Abe|Shinji|S|', 'Ogasawara|Satoshi|S|', 'Fujii|Yuki|Y|', 'Oki|Hiroharu|H|', 'Fukayama|Masashi|M|', 'Nishioka|Yasuhiko|Y|', 'Kaneko|Mika K|MK|']
D000818:Animals D000911:Antibodies, Monoclonal D058846:Antibodies, Monoclonal, Murine-Derived D000920:Antibody-Dependent Cell Cytotoxicity D016466:CHO Cells D045744:Cell Line, Tumor D006224:Cricetinae D003412:Cricetulus D000939:Epitopes D005260:Female D057809:HEK293 Cells D006801:Humans D008175:Lung Neoplasms D008562:Membrane Glycoproteins D051379:Mice D008807:Mice, Inbred BALB C D008819:Mice, Nude D009362:Neoplasm Metastasis D014162:Transfection
podoplanin metastasis PDPN monoclonal antibody ADCC/CDC