A cancer-specific anti-podocalyxin monoclonal antibody (60-mG _2a-f) exerts antitumor effects in mouse xenograft models of pancreatic carcinoma

Abstract

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 IgG _2a-type mAb, named as 60-mG _2a, to add antibody-dependent cellular cytotoxicity (ADCC). We further developed a core fucose-deficient type of 60-mG _2a, named as 60-mG _2a-f, to augment its ADCC activity. In vivo analysis revealed that 60-mG _2a-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-mG _2a-f could be useful for antibody-based therapy against PODXL-expressing pancreatic cancers.

Highlights

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  PODXL is associated with poor outcomes in several cancers.

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  We developed an anti-PODXL cancer-specific mAb (PcMab-60).

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  A core fucose-deficient IgG _2a type of PcMab-60 (60-mG _2a-f) exerted antitumor activity in MIA PaCa-2 xenograft models.

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  60-mG _2a-f could be useful for antibody-based therapy against PODXL-expressing pancreatic cancers.