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The glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells

Author

Listed:
  • Weihua Tian

    (University of Copenhagen)

  • Zilu Ye

    (University of Copenhagen)

  • Shengjun Wang

    (University of Copenhagen)

  • Morten Alder Schulz

    (University of Copenhagen)

  • Julie Coillie

    (University of Copenhagen)

  • Lingbo Sun

    (University of Copenhagen)

  • Yen-Hsi Chen

    (University of Copenhagen)

  • Yoshiki Narimatsu

    (University of Copenhagen)

  • Lars Hansen

    (University of Copenhagen)

  • Claus Kristensen

    (GlycoDisplay ApS)

  • Ulla Mandel

    (University of Copenhagen)

  • Eric Paul Bennett

    (University of Copenhagen)

  • Siamak Jabbarzadeh-Tabrizi

    (Baylor Scott & White Research Institute)

  • Raphael Schiffmann

    (Baylor Scott & White Research Institute)

  • Jin-Song Shen

    (Baylor Scott & White Research Institute)

  • Sergey Y. Vakhrushev

    (University of Copenhagen)

  • Henrik Clausen

    (University of Copenhagen)

  • Zhang Yang

    (University of Copenhagen)

Abstract

Lysosomal replacement enzymes are essential therapeutic options for rare congenital lysosomal enzyme deficiencies, but enzymes in clinical use are only partially effective due to short circulatory half-life and inefficient biodistribution. Replacement enzymes are primarily taken up by cell surface glycan receptors, and glycan structures influence uptake, biodistribution, and circulation time. It has not been possible to design and systematically study effects of different glycan features. Here we present a comprehensive gene engineering screen in Chinese hamster ovary cells that enables production of lysosomal enzymes with N-glycans custom designed to affect key glycan features guiding cellular uptake and circulation. We demonstrate distinct circulation time and organ distribution of selected glycoforms of α-galactosidase A in a Fabry disease mouse model, and find that an α2-3 sialylated glycoform designed to eliminate uptake by the mannose 6-phosphate and mannose receptors exhibits improved circulation time and targeting to hard-to-reach organs such as heart. The developed design matrix and engineered CHO cell lines enables systematic studies towards improving enzyme replacement therapeutics.

Suggested Citation

  • Weihua Tian & Zilu Ye & Shengjun Wang & Morten Alder Schulz & Julie Coillie & Lingbo Sun & Yen-Hsi Chen & Yoshiki Narimatsu & Lars Hansen & Claus Kristensen & Ulla Mandel & Eric Paul Bennett & Siamak , 2019. "The glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09809-3
    DOI: 10.1038/s41467-019-09809-3
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    Cited by:

    1. Daniel Madriz Sørensen & Christian Büll & Thomas D. Madsen & Erandi Lira-Navarrete & Thomas Mandel Clausen & Alex E. Clark & Aaron F. Garretson & Richard Karlsson & Johan F. A. Pijnenborg & Xin Yin & , 2023. "Identification of global inhibitors of cellular glycosylation," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Thapakorn Jaroentomeechai & Richard Karlsson & Felix Goerdeler & Fallen Kai Yik Teoh & Magnus Nørregaard Grønset & Dylan Wit & Yen-Hsi Chen & Sanae Furukawa & Venetia Psomiadou & Ramon Hurtado-Guerrer, 2024. "Mammalian cell-based production of glycans, glycopeptides and glycomodules," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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