期刊
CANCER MEDICINE
卷 6, 期 4, 页码 768-777出版社
WILEY
DOI: 10.1002/cam4.1049
关键词
Antibody-dependent cellular cytotoxicity; chimeric antibody; human podoplanin; monoclonal antibody
类别
资金
- Basic Science and Platform Technology Program for Innovative Biological Medicine from Japan Agency for Medical Research and Development, AMED
- Translational Research Network Program from AMED
- Platform for Drug Discovery, Informatics, and Structural Life Science (PDIS) from AMED
- Project for utilizing glycans in the development of innovative drug discovery technologies from AMED
- Regional Innovation Strategy Support Program from Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan
- JSPS KAKENHI [26440019, 16K08372, 16K10748]
- Grants-in-Aid for Scientific Research [16K08372, 16K10748, 16H05309, 26440019, 17K15611] Funding Source: KAKEN
Human podoplanin (hPDPN), a platelet aggregation-inducing transmembrane glycoprotein, is expressed in different types of tumors, and it binds to C-type lectin-like receptor 2 (CLEC-2). The overexpression of hPDPN is involved in invasion and metastasis. Anti-hPDPN monoclonal antibodies (mAbs) such as NZ-1 have shown antitumor and antimetastatic activities by binding to the platelet aggregation-stimulating (PLAG) domain of hPDPN. Recently, we developed a novel mouse anti-hPDPN mAb, LpMab-2, using the cancer-specific mAb (CasMab) technology. In this study we developed chLpMab-2, a human-mouse chimeric anti-hPDPN antibody, derived from LpMab-2. chLpMab-2 was produced using fucosyltransferase 8-knockout (KO) Chinese hamster ovary (CHO)-S cell lines. By flow cytometry, chLpMab-2 reacted with hPDPN-expressing cancer cell lines including glioblastomas, mesotheliomas, and lung cancers. However, it showed low reaction with normal cell lines such as lymphatic endothelial and renal epithelial cells. Moreover, chLpMab-2 exhibited high antibody-dependent cellular cytotoxicity (ADCC) against PDPN-expressing cells, despite its low complement-dependent cytotoxicity. Furthermore, treatment with chLpMab-2 abolished tumor growth in xenograft models of CHO/hPDPN, indicating that chLpMab-2 suppressed tumor development via ADCC. In conclusion, chLpMab-2 could be useful as a novel antibody-based therapy against hPDPN-expressing tumors.
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