Abstract
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.
Highlights
Production of chLpMab-2 We developed chLpMab-2 from a mouse monoclonal antibodies (mAbs), LpMab-2 . chLpMab-2 reacted with LN229/Human podoplanin (hPDPN) cells as revealed by flow cytometry (Fig. 1A). chLpMab-2 detected endogenous hPDPN in glioblastoma cell line LN319 and not in the LN319/hPDPN-KO cells (PDIS-6) (Fig. 1B)
Our results showed that chLpMab-2 was specific against hPDPN
(chLpMab-7) [40] and human–rat chimeric anti-hPDPN antibodies such as NZ-8 [36] and NZ-12 [37]
Summary
Human podoplanin (hPDPN), known as hT1α, hAggrus, or gp, is expressed in many types of cancers, such as malignant brain tumors, malignant mesotheliomas, lung cancers, esophageal cancers, testicular tumors, bladder cancers, osteosarcomas, and fibrosarcomas [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]. hPDPN expression is observed only in squamous cell carcinomas of lung and esophageal cancers, indicating that hPDPN exhibits histological type-specific expression. HPDPN is highly expressed in normal lymphatic endothelial cells (LECs) and normal lung type-I alveolar cells at the same level as in cancer cells. NZ-1 mediates antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against tumor cells that express hPDPN [36]. Human–rat chimeric antibodies, such as NZ-8 and NZ-12, exhibit high ADCC and CDC in vitro, and they show very high antitumor activities and neutralizing capabilities [36, 37]. These chimeric mAbs are not cancer-specific; cancer-specific anti-hPDPN chimeric or humanized antibodies should be developed to prevent unfavorable side effects
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