A Novel Targeting Therapy of Malignant Mesothelioma Using Anti-Podoplanin Antibody

Abe, Shinji; Morita, Yuki; Kaneko, Mika K.; Hashimoto, Masaki; Tsujimoto, Yuta; Goto, Hisatsugu; Kakiuchi, Soji; Aono, Yoshinori; Huang, Jun; Sato, Seidai; Kishuku, Masatoshi; Taniguchi, Yuki; Azuma, Mami; Kawazoe, Kazuyoshi; Sekido, Yoshitaka; Yano, Seiji; Akiyama, Shin Ichi; Sone, Saburo; Minakuchi, Kazuo; Kato, Yoshinori; Nishioka, Yasuhiko

doi:10.4049/jimmunol.1300448

Cited by 84 publications

(92 citation statements)

References 50 publications

(42 reference statements)

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“…(19) Rat-human chimeric antipodoplanin antibody (NZ-8), which was produced from NZ-1, possesses antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against podoplanin-expressing glioblastoma or malignant mesothelioma cell lines. (15,29) Unexpectedly, the intensity of NZ-1 was very weak in metastatic lesions of osteosarcomas in this study, probably because (1) the NZ-1 epitope (42-47 amino acids) (20) was blocked by the attachment of glycan complex to podoplanin; (2) CLEC-2 or other counterparts inhibited the NZ-1 binding to PLAG domain; and (3) the conformation of podoplanin at metastatic lesions is different from that at primary lesions. In contrast, a novel anti-podoplanin MAb, LpMab-7, detects podoplanin not only at primary lesions but also at metastatic lesions of osteosarcomas, although the binding affinity of LpMab-7 (K D = 5.7 · 10 -10 M in ELISA and K D = 2.0 · 10 -8 M in flow cytometry) is lower than NZ-1.…”

Section: Discussionmentioning

confidence: 52%

“…(6,7) Expression of podoplanin has been reported in many tumors. (6,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) Several studies have reported that osteosarcoma tissues and cell lines such HOS, U-2 OS, and MG-63 express podoplanin. (17) Moreover, podoplanin expression was reported to be involved in the poor prognosis of osteosarcoma patients.…”

Section: Introductionmentioning

confidence: 99%

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Anti-podoplanin Monoclonal Antibody LpMab-7 Detects Metastatic Lesions of Osteosarcoma

Kaneko

Oki

Ogasawara

et al. 2015

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

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Osteosarcoma is the most common primary malignant bone tumor and is highly metastatic to the lungs. Therefore, the development of a novel molecular targeting therapy against metastasis of osteosarcoma is necessary. A platelet aggregation-inducing factor, podoplanin/aggrus, is involved in tumor metastasis. Furthermore, podoplanin expression was reported to be involved in the poor prognosis of osteosarcoma patients. However, the association between podoplanin expression and metastasis of osteosarcoma remains unclear because of the lack of highly sensitive anti-podoplanin monoclonal antibodies (MAbs). In this study, we used a novel anti-podoplanin MAb, LpMab-7, which is more sensitive than well-known anti-podoplanin MAbs in immunohistochemistry. Immunohistochemical analysis using LpMab-7 showed that podoplanin expression at primary lesions is observed in 15 out of 16 (93.8%) cases. Furthermore, podoplanin expression at metastatic lesions was higher compared with primary lesions in three out of four (75%) cases with lung metastasis. Because LpMab-7 has high sensitivity against podoplanin, it is expected to be useful for molecular targeting therapy for osteosarcomas.

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Section: Discussionmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Anti-podoplanin Monoclonal Antibody LpMab-7 Detects Metastatic Lesions of Osteosarcoma

Kaneko

Oki

Ogasawara

et al. 2015

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

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“…In the present study, we showed that the novel CTC-chip can capture mesothelioma cells (ACC-MESO-1) when coated with an antibody against podoplanin that is a specific antigen expressed on the surface of mesothelial cells (17)(18)(19). In the previous study, we showed that the 'podoplanin-chip' effectively captured mesothelioma cells of another cell line, ACC-MESO-4 (15), indicating that the novel CTC-chip is a promising modality to detect some kinds of tumor cells including EpCAM-negative cells due to non-epithelial origin (e.g., mesothelioma cells) or undergoing epithelial-mesenchymal transition (EMT).…”

Section: Discussionmentioning

confidence: 78%

Capture of mesothelioma cells with ‘universal’ CTC-chip

et al. 2017

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Abstract. Malignant mesothelioma (MM) is a highly aggressive malignant tumor, predominantly associated with job-related exposure to asbestos. Development of effective and non-invasive modalities for diagnosis is an important issue in occupational medicine. Circulating tumor cells (CTCs), which are tumor cells that are shed from primary tumors and circulate in the peripheral blood, may be detected at an earlier stage than malignant tumors, and detection of CTCs may provide a novel insight into the diagnosis of MM. In a previous study evaluating clinical utility of CTCs, detected with a widely used system 'CellSearch', the authors indicated a significant however insufficient capability in the diagnosis of MM, suggesting need for a more sensitive system. Accordingly, the authors developed a novel microfluidic system to capture CTCs (CTC-chip), and demonstrated that the CTC-chip effectively captured MM cells (ACC-MESO-4) spiked in the blood by conjugating an anti-podoplanin antibody. The results of the present study demonstrated that the CTC-chip coated with the anti-podoplanin antibody captured another MM cell (ACC-MESO-1). However, the capture efficiencies were lower than those for ACC-MESO-4. In addition, an anti-mesothelin antibody was used to capture CTCs, however the CTC-chip coated with the anti-mesothelin antibody failed to effectively capture MM cells, possibly due to low mesothelin expression. Overall, the CTC-chip may capture specific types of CTCs by conjugating any antibody against an antigen expressed on CTCs, and may be a useful system for the diagnosis of malignant tumors, including MM.

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“…P odoplanin (PDPN), the endogenous ligand of C-type lectin-like receptor-2 (CLEC-2) of platelet, (1,2) is highly expressed not only in many tumors, including malignant brain tumor, mesothelioma, oral cancer, lung cancer, esophageal cancer, testicular tumor, and osteosarcoma (OS), (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) but also in normal cells such as lymphatic endothelial cells (LEC). (14,15) ''Podoplanin'' was named after its expression in podocytes of kidney.…”

Section: Introductionmentioning

confidence: 99%

Establishment of Mouse Monoclonal Antibody LpMab-13 Against Human Podoplanin

OgasawaraSatoshi

Kaneko

HonmaRyusuke

et al. 2016

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

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Podoplanin (PDPN)/Aggrus is a type-I transmembrane sialoglycoprotein, which possesses a platelet aggregation-stimulating (PLAG) domain. The O-glycosylation on Thr52 of human PDPN (hPDPN) is critical for the interaction of hPDPN with C-type lectin-like receptor-2 (CLEC-2), resulting in platelet aggregation. Many anti-hPDPN monoclonal antibodies (MAbs) against PLAG domains and non-PLAG domains have been established; however, mouse anti-PLAG2/3 MAb, the epitope of which is consistent with rat anti-PLAG2/3 MAb NZ-1, has not been established. NZ-1 inhibits the hPDPN-CLEC-2 interaction and is also useful for anti-PA tag MAb. We recently established CasMab technology to produce MAbs against membranous proteins. Herein, we produced a novel anti-hPDPN MAb, LpMab-13, which binds to PLAG2/3 domains. LpMab-13 recognized endogenous hPDPN of cancer cells, including glioblastoma, oral cancer, lung cancer, and malignant mesothelioma, and normal cells such as lymphatic endothelial cells and podocytes of kidney in Western blot, flow cytometry, and immunohistochemistry. LpMab-13 recognized glycan-deficient hPDPN in flow cytometry, indicating that the interaction between LpMab-13 and hPDPN is independent of its glycosylation. The minimum epitope of LpMab-13 was identified as Ala42-Asp49 of hPDPN using Western blot and flow cytometry. The combination of different epitope-possessing MAbs could be advantageous for the hPDPN-targeting diagnosis and therapy.

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A Novel Targeting Therapy of Malignant Mesothelioma Using Anti-Podoplanin Antibody

Cited by 84 publications

References 50 publications

Anti-podoplanin Monoclonal Antibody LpMab-7 Detects Metastatic Lesions of Osteosarcoma

Anti-podoplanin Monoclonal Antibody LpMab-7 Detects Metastatic Lesions of Osteosarcoma

Capture of mesothelioma cells with ‘universal’ CTC-chip

Establishment of Mouse Monoclonal Antibody LpMab-13 Against Human Podoplanin

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