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

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 Jabbarzadeh-Tabrizi, Raphael Schiffmann, Jin-Song Shen, Sergey Y. Vakhrushev, Henrik Clausen () and Zhang Yang ()
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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

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09809-3

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