title: Towards controlling the glycoform: a model framework linking extracellular metabolites to antibody glycosylation.
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.
authors.affiliation: Centre for Process Systems Engineering, Department of Chemical Engineering, Imperial College London, London SW7 2AZ, UK. philip.jedrzejewski07@imperial.ac.uk.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Jedrzejewski
authors.affiliation: Centre for Process Systems Engineering, Department of Chemical Engineering, Imperial College London, London SW7 2AZ, UK. ioscani.jimenez-del-val06@imperial.ac.uk.
authors.forename: Ioscani Jimenez
authors.initials: IJ
authors.lastname: del Val
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK. a.constantinou@imperial.ac.uk.
authors.forename: Antony
authors.initials: A
authors.lastname: Constantinou
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK. a.dell@imperial.ac.uk.
authors.forename: Anne
authors.initials: A
authors.lastname: Dell
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK. s.haslam@imperial.ac.uk.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Haslam
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK. k.polizzi@imperial.ac.uk.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Polizzi
authors.affiliation: Centre for Process Systems Engineering, Department of Chemical Engineering, Imperial College London, London SW7 2AZ, UK. cleo.kontoravdi@imperial.ac.uk.
authors.forename: Cleo
authors.initials: C
authors.lastname: Kontoravdi
mesh_terms: D000465:Algorithms; D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D003198:Computer Simulation; D005110:Extracellular Space / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D006825:Hybridomas; D053858:Metabolic Networks and Pathways; D051379:Mice; D008954:Models, Biological; D009702:Nucleoside Diphosphate Sugars / Q000378:metabolism; D009711:Nucleotides / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013997:Time Factors
chemical_list: D000906:Antibodies; D006023:Glycoproteins; D009702:Nucleoside Diphosphate Sugars; D009711:Nucleotides; D011134:Polysaccharides; D005973:Glutamine; D005947:Glucose