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.
Highlights
Podoplanin (PDPN/Aggrus/T1α) is a platelet aggregation-inducing type I transmembrane O-glycoprotein [1,2,3]
We previously produced a novel anti-human PDPN (hPDPN) monoclonal antibodies (mAbs), LpMab-7 (IgG1, kappa) [31], and identified the minimum epitope of LpMab-7 as Arg79-Leu83 of hPDPN (162 amino acids), which is distinct from the platelet aggregation-stimulating (PLAG) domain [32]
We first determined whether LpMab-7 inhibits hPDPNCLEC-2 interaction using enzymelinked immunosorbent assay (ELISA)
Summary
Podoplanin (PDPN/Aggrus/T1α) is a platelet aggregation-inducing type I transmembrane O-glycoprotein [1,2,3]. We previously compared the migration activities of PDPN-transfected osteosarcoma cells and parental cells and found that PDPN-transfected osteosarcoma cells exhibited a higher migration activity [14]. In solid tumors such as brain tumors, only a small and phenotypically distinct subset of cells can be responsible for generating and sustaining tumors, and these cells are considered cancer stem cells [22]. PDPN has been reported to be a cancer stem cell marker [24]; immunotherapy using specific antibodies against hPDPN may eradicate cancer stem cells in cancers
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