TY - JOUR
T1 - A cancer-specific anti-podocalyxin monoclonal antibody (60-mG2a-f) exerts antitumor effects in mouse xenograft models of pancreatic carcinoma
AU - Kaneko, Mika K.
AU - Ohishi, Tomokazu
AU - Kawada, Manabu
AU - Kato, Yukinari
N1 - Funding Information:
This research was supported in part by AMED under Grant Numbers: JP20am0401013 (Y.K.), JP20am0101078 (Y.K.), JP20ae0101028 (Y.K.), and JP20bm1004001 (Y.K.), and by JSPS KAKENHI Grant Numbers: 17K07299 (M.K.K.) and 19K07705 (Y.K.).
Publisher Copyright:
© 2020 The Authors
PY - 2020/12
Y1 - 2020/12
N2 - Overexpression of podocalyxin (PODXL) is associated with progression, metastasis, and poor outcomes in several cancers. PODXL also plays an important role in the development of normal tissues. For antibody-based therapy to target PODXL-expressing cancers using monoclonal antibodies (mAbs), cancer-specificity is necessary to reduce the risk of adverse effects to normal tissues. In this study, we developed an anti-PODXL cancer-specific mAb (CasMab), named as PcMab-60 (IgM, kappa) by immunizing mice with soluble PODXL, which is overexpressed in LN229 glioblastoma cells. The PcMab-60 reacted with the PODXL-overexpressing LN229 (LN229/PODXL) cells and MIA PaCa-2 pancreatic cancer cells in flow cytometry but did not react with normal vascular endothelial cells (VECs), whereas one of non-CasMabs, PcMab-47 showed high reactivity for not only LN229/PODXL and MIA PaCa-2 cells but also VECs, indicating that PcMab-60 is a CasMab. Next, we engineered PcMab-60 into a mouse IgG2a-type mAb, named as 60-mG2a, to add antibody-dependent cellular cytotoxicity (ADCC). We further developed a core fucose-deficient type of 60-mG2a, named as 60-mG2a-f, to augment its ADCC activity. In vivo analysis revealed that 60-mG2a-f exerted antitumor activity in MIA PaCa-2 xenograft models at a dose of 100 μg/mouse/week administered three times. These results suggested that 60-mG2a-f could be useful for antibody-based therapy against PODXL-expressing pancreatic cancers.
AB - Overexpression of podocalyxin (PODXL) is associated with progression, metastasis, and poor outcomes in several cancers. PODXL also plays an important role in the development of normal tissues. For antibody-based therapy to target PODXL-expressing cancers using monoclonal antibodies (mAbs), cancer-specificity is necessary to reduce the risk of adverse effects to normal tissues. In this study, we developed an anti-PODXL cancer-specific mAb (CasMab), named as PcMab-60 (IgM, kappa) by immunizing mice with soluble PODXL, which is overexpressed in LN229 glioblastoma cells. The PcMab-60 reacted with the PODXL-overexpressing LN229 (LN229/PODXL) cells and MIA PaCa-2 pancreatic cancer cells in flow cytometry but did not react with normal vascular endothelial cells (VECs), whereas one of non-CasMabs, PcMab-47 showed high reactivity for not only LN229/PODXL and MIA PaCa-2 cells but also VECs, indicating that PcMab-60 is a CasMab. Next, we engineered PcMab-60 into a mouse IgG2a-type mAb, named as 60-mG2a, to add antibody-dependent cellular cytotoxicity (ADCC). We further developed a core fucose-deficient type of 60-mG2a, named as 60-mG2a-f, to augment its ADCC activity. In vivo analysis revealed that 60-mG2a-f exerted antitumor activity in MIA PaCa-2 xenograft models at a dose of 100 μg/mouse/week administered three times. These results suggested that 60-mG2a-f could be useful for antibody-based therapy against PODXL-expressing pancreatic cancers.
KW - Cancer-specific mAb
KW - Monoclonal antibody
KW - PODXL
KW - Pancreatic cancer
KW - Podocalyxin
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UR - http://www.scopus.com/inward/citedby.url?scp=85092539202&partnerID=8YFLogxK
U2 - 10.1016/j.bbrep.2020.100826
DO - 10.1016/j.bbrep.2020.100826
M3 - Article
AN - SCOPUS:85092539202
SN - 2405-5808
VL - 24
JO - Biochemistry and Biophysics Reports
JF - Biochemistry and Biophysics Reports
M1 - 100826
ER -
