The chimeric antibody chLpMab-7 targeting human podoplanin suppresses pulmonary metastasis via ADCC and CDC rather than via its neutralizing activity

Yukinari Kato, Akiko Kunita, Shinji Abe, Satoshi Ogasawara, Yuki Fujii, Hiroharu Oki, Masashi Fukayama, Yasuhiko Nishioka, Mika K. Kaneko

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)

Abstract

Podoplanin (PDPN/Aggrus/T1a) 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 antihuman 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.

Original languageEnglish
Pages (from-to)36003-36018
Number of pages16
JournalOncotarget
Volume6
Issue number34
DOIs
Publication statusPublished - 2015
Externally publishedYes

Keywords

  • ADCC/CDC
  • Metastasis
  • Monoclonal antibody
  • PDPN
  • Podoplanin

ASJC Scopus subject areas

  • Oncology

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