The chimeric antibody chLpMab-7 targeting human podoplanin suppresses pulmonary metastasis via ADCC and CDC rather than via its neutralizing activity
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Yukinari Kato1,*, Akiko Kunita2,*, Shinji Abe3,*, Satoshi Ogasawara1, Yuki Fujii1, Hiroharu Oki1, Masashi Fukayama2, Yasuhiko Nishioka4, Mika K. Kaneko1
1Department of Regional Innovation, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8575, Japan
2Department of Pathology, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
3Department of Clinical Pharmacy Practice Pedagogy, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8505, Japan
4Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
*These authors have contributed equally to this work
Yukinari Kato, e-mail: [email protected], [email protected]
Keywords: podoplanin, PDPN, metastasis, monoclonal antibody, ADCC/CDC
Received: June 07, 2015 Accepted: September 14, 2015 Published: September 25, 2015
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.
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