The glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
The glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells. / 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.
In: Nature Communications, Vol. 10, 1785, 2019.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - The glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells
AU - Tian, Weihua
AU - Ye, Zilu
AU - Wang, Shengjun
AU - Schulz, Morten Alder
AU - Van Coillie, Julie
AU - Sun, Lingbo
AU - Chen, Yen-Hsi
AU - Narimatsu, Yoshiki
AU - Hansen, Lars
AU - Kristensen, Claus
AU - Mandel, Ulla
AU - Bennett, Eric Paul
AU - Jabbarzadeh-Tabrizi, Siamak
AU - Schiffmann, Raphael
AU - Shen, Jin-Song
AU - Vakhrushev, Sergey Y.
AU - Clausen, Henrik
AU - Yang, Zhang
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Animals
KW - CHO Cells
KW - Cricetinae
KW - Cricetulus
KW - Disease Models, Animal
KW - Fabry Disease/drug therapy
KW - Glycosylation
KW - Lysosomes/enzymology
KW - Male
KW - Mice
KW - Mice, Knockout
KW - Recombinant Proteins/therapeutic use
KW - alpha-Galactosidase/therapeutic use
U2 - 10.1038/s41467-019-09809-3
DO - 10.1038/s41467-019-09809-3
M3 - Journal article
C2 - 31040271
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 1785
ER -
ID: 221852611