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

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 g...

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Published inNature communications Vol. 10; no. 1; p. 1785
Main Authors Tian, Weihua, Ye, Zilu, Wang, Shengjun, Schulz, Morten Alder, Van Coillie, Julie, Sun, Lingbo, Chen, Yen-Hsi, Narimatsu, Yoshiki, Hansen, Lars, Kristensen, Claus, Mandel, Ulla, Bennett, Eric Paul, Jabbarzadeh-Tabrizi, Siamak, Schiffmann, Raphael, Shen, Jin-Song, Vakhrushev, Sergey Y., Clausen, Henrik, Yang, Zhang
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 30.04.2019
Nature Publishing Group
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Summary: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. Lysosomal replacement enzymes are taken up by cell surface receptors that recognize glycans, the effects of different glycan features are unknown. Here the authors present a gene engineering screen in CHO cells that allows custom N-glycan-decorated enzymes with improved circulation time and organ distribution.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-019-09809-3