Experimental and In Silico Modelling Analyses of the Gene Expression Pathway for Recombinant Antibody and By-Product Production in NS0 Cell Lines 英文参考文献.docVIP

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Experimental and In Silico Modelling Analyses of the Gene Expression Pathway for Recombinant Antibody and By-Product Production in NS0 Cell Lines 英文参考文献.doc

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Experimental and In Silico Modelling Analyses of the Gene Expression Pathway for Recombinant Antibody and By-Product Production in NS0 Cell Lines 英文参考文献

ExperimentalandInSilicoModellingAnalysesofthe GeneExpressionPathwayforRecombinantAntibody andBy-ProductProductioninNS0CellLines EmmaJ.Mead1,3*,LesleyM.Chiverton1,3,SarahK.Spurgeon2,3,ElaineB.Martin4,GaryA.Montague4 ,C. MarkSmales1,3*,TobiasvonderHaar1,3 * 1School of Biosciences, University of Kent, Canterbury, United Kingdom, 2School of Engineering and Digital Arts, University of Kent, Canterbury, United Kingdom, 3Centre for Molecular Processing, University of Kent, Canterbury, United Kingdom, 4School of Chemical Engineering and Advanced Materials, Newcastle University, Newcastle,UnitedKingdom Abstract Monoclonalantibodiesarecommerciallyimportant,highvaluebiotherapeuticdrugsusedinthetreatmentofavarietyof diseases. These complex molecules consist of two heavy chain and two light chain polypeptides covalently linked by disulphidebonds.Theyareusuallyexpressedasrecombinantproteinsfromculturedmammaliancells,whicharecapableof correctlymodifying,foldingandassemblingthepolypeptidechainsintothenativequaternarystructure.Suchrecombinant celllinesoftenvaryintheamountsofproductproducedandintheheterogeneityofthesecretedproducts.Thebiological mechanisms of this variation are not fully defined. Here we have utilised experimental and modelling strategies to characteriseanddefinethebiologyunderpinningproductheterogeneityincelllinesexhibitingvaryingantibodyexpression levels,andthenexperimentallyvalidatedthesemodels.Inundertakingthesestudiesweappliedandvalidatedbiochemical (rate-constantbased)andengineering(nonlinear)modelsofantibodyexpressiontoexperimentaldatafromfourNS0cell lines with different IgG4 secretion rates. The models predict that export of the full antibody and its fragments are intrinsicallylinked,andcannotthereforebemanipulatedindividuallyatthelevelofthesecretorymachinery.Instead,the modelshighlightstrategiesforthemanipulationattheprecursorspeciesleveltoincreaserecombinantproteinyieldsin bothhighandlowproducingcelllines.Themodelsalsohighlightcelllinespecificlimitationsi