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Protein Glycosylation Control in Mammalian Cell Culture: Past Precedents and Contemporary Prospects

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Genomics and Systems Biology of Mammalian Cell Culture

Part of the book series: Advances in Biochemical Engineering Biotechnology ((ABE,volume 127))

Abstract

Protein glycosylation is a post-translational modification of paramount importance for the function, immunogenicity, and efficacy of recombinant glycoprotein therapeutics. Within the repertoire of post-translational modifications, glycosylation stands out as having the most significant proven role towards affecting pharmacokinetics and protein physiochemical characteristics. In mammalian cell culture, the understanding and controllability of the glycosylation metabolic pathway has achieved numerous successes. However, there is still much that we do not know about the regulation of the pathway. One of the frequent conclusions regarding protein glycosylation control is that it needs to be studied on a case-by-case basis since there are often conflicting results with respect to a control variable and the resulting glycosylation. In attempts to obtain a more multivariate interpretation of these potentially controlling variables, gene expression analysis and systems biology have been used to study protein glycosylation in mammalian cell culture. Gene expression analysis has provided information on how glycosylation pathway genes both respond to culture environmental cues, and potentially facilitate changes in the final glycoform profile. Systems biology has allowed researchers to model the pathway as well-defined, inter-connected systems, allowing for the in silico testing of pathway parameters that would be difficult to test experimentally. Both approaches have facilitated a macroscopic and microscopic perspective on protein glycosylation control. These tools have and will continue to enhance our understanding and capability of producing optimal glycoform profiles on a consistent basis.

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Abbreviations

ADCC:

Antibody-dependent cellular cytotoxicity

BHK:

Baby hamster kidney cells

CDC:

Complement-dependent cytotoxicity

CHO:

Chinese hamster ovary cells

CMP-NeuAc:

Cytosine monophosphate-N-acetylneuraminic acid

DO:

Dissolved oxygen

EPO:

Erythropoietin

ER:

Endoplasmic reticulum

Fuc:

Fucose

FucT:

Glycoprotein 6-α-L-fucosyltransferase

Gal:

Galactose

GalNAc:

N-Acetylgalactosamine

GalT:

β-N-Acetylglucosaminyl glycopeptide β-1,4-galactosyltransferase

GDP-Fuc:

Guanidine diphosphate-fucose

GlcNAc:

N-Acetylglucosamine

GnT I:

α-1,3-Mannosyl-glycoprotein 2-β-N-acetylglucosaminyltransferase

GnT II:

α-1,6-Mannosyl-glycoprotein 2-β-N-acetylglucosaminyltransferase

GnT III:

β-1,4-Mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase

GnT IV:

α-1,3-Mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase

GnT V:

α-1,6-Mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase

GS:

Glutamine synthetase

IFN-γ:

Interferon-gamma

Man:

Mannose

Man I:

Mannosyl-oligosaccharide 1,2-α-mannosidase

Man II:

Mannosyl-oligosaccharide 1,3-1,6-α-mannosidase

ManNAc:

N-Acetylmannosamine

NeuAc:

N-Acetylneuraminic acid (sialic acid)

NeuGc:

N-Glycolylneuraminic acid

PK:

Pharmacokinetics

PCA:

Principal component analysis

tPA:

Tissue plasminogen activator

SiaT:

β-Galactoside α-2,3/6-sialyltransferase

UDP-Gal:

Uridine diphosphate-galactose

UDP-GlcNAc:

Uridine diphosphate-N-acetylglucosamine

UPR:

Unfolded protein response

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Acknowledgments

Content review and helpful suggestions from Sean McDermott and Christopher Racicot is gratefully acknowledged.

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  1. Abbott Laboratories, Abbott Bioresearch Center, Worcester, MA, 01605, USA

    Patrick Hossler

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  1. , Dept. Chemical Engineering and Material, University of Minnesota, Washington Ave. SE 421, Minneapolis, 55455, Minnesota, USA

    Wei Shou Hu

  2. , Institut für Bioprozess- und Biosystemte, Technische Universität Hamburg-Harburg, Denickestr. 15, Hamburg, 21073, Germany

    An-Ping Zeng

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Hossler, P. (2011). Protein Glycosylation Control in Mammalian Cell Culture: Past Precedents and Contemporary Prospects. In: Hu, W., Zeng, AP. (eds) Genomics and Systems Biology of Mammalian Cell Culture. Advances in Biochemical Engineering Biotechnology, vol 127. Springer, Berlin, Heidelberg. https://doi.org/10.1007/10_2011_113

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