ID 113062
Author
Itai, Shunsuke Tohoku University|Tokyo Medical and Dental University
Ohishi, Tomokazu Microbial Chemistry Research Foundation
Kaneko, Mika K. Tohoku University
Yamada, Shinji Tohoku University
Nakamura, Takuro Tohoku University
Yanaka, Miyuki Tohoku University
Chang, Yao-Wen Tohoku University
Ohba, Shun-Ichi Institute of Microbial Chemistry
Kawada, Manabu Microbial Chemistry Research Foundation
Harada, Hiroyuki Tokyo Medical and Dental University
Kato, Yukinari Tohoku University
Keywords
podocalyxin
PODXL
monoclonal antibody
antibody-dependent cellular cytotoxicity
oral squamous cell carcinoma
Content Type
Journal Article
Description
Podocalyxin (PODXL) overexpression is associated with progression, metastasis, and poor outcomes in cancers. We recently produced the novel anti-PODXL monoclonal antibody (mAb) PcMab-47 (IgG1, kappa). Herein, we engineered PcMab-47 into 47-mG2a, a mouse IgG2a-type mAb, to add antibody-dependent cellular cytotoxicity (ADCC). We further developed 47-mG2a-f, a core fucose-deficient type of 47-mG2a to augment its ADCC. Immunohistochemical analysis of oral cancer tissues using PcMab-47 and 47-mG2a revealed that the latter stained oral squamous cell carcinoma (OSCC) cells in a cytoplasmic pattern at a much lower concentration. PcMab-47 and 47-mG2a detected PODXL in 163/201 (81.1%) and in 197/201 (98.0%) OSCC samples, respectively. 47-mG2a-f also detected PODXL in OSCCs at a similar frequency as 47-mG2a. In vitro analysis revealed that both 47-mG2a and 47-mG2a-f exhibited strong complement-dependent cytotoxicity (CDC) against CHO/hPODXL cells. In contrast, 47-mG2a-f exhibited much stronger ADCC than 47-mG2a against OSCC cells, indicating that ADCC and CDC of those anti-PODXL mAbs depend on target cells. In vivo analysis revealed that both 47-mG2a and 47-mG2a-f exerted antitumor activity in CHO/hPODXL xenograft models at a dose of 100 μg or 500 μg/mouse/week administered twice. 47-mG2a-f, but not 47-mG2a, exerted antitumor activity in SAS and HSC-2 xenograft models at a dose of 100 μg/mouse/week administered three times. Although both 47-mG2a and 47-mG2a-f exerted antitumor activity in HSC-2 xenograft models at a dose of 500 μg/mouse/week administered twice, 47-mG2a-f also showed higher antitumor activity than 47-mG2a. These results suggested that a core fucose-deficient anti-PODXL mAb could be useful for antibody-based therapy against PODXL-expressing OSCCs.
Journal Title
Oncotarget
ISSN
19492553
Publisher
Impact Journals, LLC
Volume
9
Issue
32
Start Page
22480
End Page
22497
Published Date
2018-04-27
Rights
Copyright: Itai et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0) (https://creativecommons.org/licenses/by/3.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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DOI (Published Version)
URL ( Publisher's Version )
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language
eng
TextVersion
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departments
Pharmaceutical Sciences
Medical Sciences