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Dynamic Control of Oligosaccharide Modification in the Mammary Gland: Linking Recombinant Human Erythropoietin

Functional Analysis of Transgenic Mouse Milk-Derived hEPO

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Abstract

We analyzed two transgenic mouse lines that secrete rhEPO in their milk to assess the dynamic control of N-linked oligosaccharides. Since pharmaceutically available epoetin α and β are produced in CHO cells, we compared transgenic mammary gland-derived rhEPO to its CHO cell-derived counterpart. The major glycosyltransferases that determine the N-oligosaccharides patterns of rhEPO include N-acetylglycosaminyltransferase (GnT) and α1,3/4 fucosyltransferase (Fuc-TIV), GnT-III, -V and Fuc-TIV expression in the mouse mammary gland is significantly higher than that in Chinese hamster ovary (CHO)-derived cells, where the protein is not detectable. The data suggest that N-linked sugar chain patterns of recombinant glycoproteins, produced by the mammary gland differ, since GnT-III alters the sugar pattern extensively. In our experiments, rhEPO produced by the transgenic mice contains more tetra-acidic oligosaccharide structures than epoetin α derived from CHO cells, a rhEPO that is widely used therapeutically. Accordingly, we examined milk-derived rhEPO activity, both in vitro and in vivo. The rhEPO protein purified from the milk of mammary glands upregulates the EPO receptor-mediated expression of the STAT5 gene in MCF-7 cells in a dose-dependent manner, similar to the effects of epoetin α. Furthermore, direct injection of rhEPO into the mouse tail vein leads to an increase in the levels of blood components, such as red blood cells and platelets. In light of these findings, we suggest that the mammary glands of transgenic animals provide a sufficient environment to generate rhEPO with post-translational modifications for biopharmaceutical use.

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  1. Department of Dairy Science, Division of Applied Life Science, College of Agriculture and Life Science, Gyeongsang National University, 660-701, Chinju, GyeongNam, Korea

    Deug-Nam Kwon, Jong-Yi Park, So-Young Lee, Seong-Keon Cho, Sung-Jo Kang & Jin-Hoi Kim

  2. Department of Animal Science, College of Natural Science, Kon-kuk University, 380-701, Chung-ju, Chung-buk, Korea

    Hyuk Song

  3. Department of Internal Medicine, College of Medicine, Gyeongsang National University, 660-70, Chinju, GyeongNam, Korea

    Joung Soon Jang

  4. Department of Pharmacology, College of Medicine, Gyeongsang National University, 660-701, Chinju, GyeongNam, Korea

    Han Geuk Seo

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  1. Deug-Nam Kwon
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Kwon, DN., Song, H., Park, JY. et al. Dynamic Control of Oligosaccharide Modification in the Mammary Gland: Linking Recombinant Human Erythropoietin. Transgenic Res 15, 37–55 (2006). https://doi.org/10.1007/s11248-005-3519-2

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