Towards controlling the glycoform: a model framework linking extracellular metabolites to antibody glycosylation
Author(s)
Type
Journal Article
Abstract
Glycoproteins represent the largest group of the growing number of biologically-derived medicines. The associated glycan structures and their distribution are known to have a large impact on pharmacokinetics. A modelling framework was developed to provide a link from the extracellular environment and its effect on intracellular metabolites to the distribution of glycans on the constant region of an antibody product. The main focus of this work is the mechanistic in silico reconstruction of the nucleotide sugar donor (NSD) metabolic network by means of 34 species mass balances and the saturation kinetics rates of the 60 metabolic reactions involved. NSDs are the co-substrates of the glycosylation process in the Golgi apparatus and their simulated dynamic intracellular concentration profiles were linked to an existing model describing the distribution of N-linked glycan structures of the antibody constant region. The modelling framework also describes the growth dynamics of the cell population by means of modified Monod kinetics. Simulation results match well to experimental data from a murine hybridoma cell line. The result is a modelling platform which is able to describe the product glycoform based on extracellular conditions. It represents a first step towards the in silico prediction of the glycoform of a biotherapeutic and provides a platform for the optimisation of bioprocess conditions with respect to product quality.
Editor(s)
Berninsone, P
Date Issued
2014-03-14
Date Acceptance
2014-02-21
Citation
International Journal of Molecular Sciences, 2014, 15 (3), pp.4492-4522
ISSN
1422-0067
Publisher
MDPI AG
Start Page
4492
End Page
4522
Journal / Book Title
International Journal of Molecular Sciences
Volume
15
Issue
3
Copyright Statement
© The Author(s). This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0 - https://creativecommons.org/licenses/by/3.0/).
Sponsor
Biotechnology and Biological Sciences Research Council (BBSRC)
Biotechnology and Biological Sciences Research Council (BBSRC)
Grant Number
BB/I017011/1
BB/K016164/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Physical Sciences
Biochemistry & Molecular Biology
Chemistry, Multidisciplinary
Chemistry
metabolic modelling
nucleotide sugars
antibody glycosylation
GLOBAL SENSITIVITY-ANALYSIS
N-GLYCOSYLATION
COMPONENT FUNCTIONS
MATHEMATICAL-MODEL
MASS-SPECTROMETRY
MAMMALIAN-CELLS
GOLGI-APPARATUS
FLUX ANALYSIS
CHO-CELLS
RS-HDMR
Algorithms
Animals
Antibodies
Cell Line
Cell Proliferation
Computer Simulation
Extracellular Space
Glucose
Glutamine
Glycoproteins
Glycosylation
Golgi Apparatus
Hybridomas
Metabolic Networks and Pathways
Mice
Models, Biological
Nucleoside Diphosphate Sugars
Nucleotides
Polysaccharides
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Time Factors
0399 Other Chemical Sciences
0604 Genetics
0699 Other Biological Sciences
Chemical Physics
Publication Status
Published
Date Publish Online
2014-03-14