Therapeutic Fc-Fusion Proteins

400 Pages·2014·7.362 MB·English

by  Steven M. Chamow, Thomas Ryll, Henry B. Lowman, Deborah Farson

Therapeutic
Fc-Fusion Proteins
Edited by Steven M. Chamow,
Thomas Ryll, Henry B. Lowman, and Deborah Farson

Editedby
StevenM.Chamow,
ThomasRyll,
HenryB.Lowman,
andDeborahFarson
TherapeuticFc-Fusion
Proteins
RelatedTitles
Dübel,S.,Reichert,J.M.(eds.) Reilly,R.M.(ed.)
HandbookofTherapeutic MonoclonalAntibodyand
Antibodies Peptide-TargetedRadiotherapy
2Edition ofCancer
2014
2010
PrintISBN:978-3-527-32937-3,alsoavailable
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Knäblein,J.(ed.)
Gottschalk,U.(ed.)
ModernBiopharmaceuticals
ProcessScalePurificationof
RecentSuccessStories
Antibodies
2013
2009
PrintISBN:978-3-527-32283-1,alsoavailable
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Bertolini,J.,Goss,N.,Curling,J.(eds.)
Schmidt,S.R.(ed.)
ProductionofPlasmaProteins
FusionProteinTechnologies
forTherapeuticUse
forBiopharmaceuticals
2013
2013
PrintISBN:978-0-470-92431-0,alsoavailable
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Kontermann,R.(ed.)
TherapeuticProteins
StrategiestoModulateTheirPlasma
Half-lives
2012
PrintISBN:978-3-527-32849-9,alsoavailable
indigitalformats
Edited by
Steven M. Chamow, Thomas Ryll, Henry B. Lowman,
and Deborah Farson
Therapeutic Fc-Fusion Proteins
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publisherandauthorhaveusedtheirbesteffortsin
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SouthSanFrancisco,CA94080 tospecial,incidental,consequential,orother
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j
V
Contents
Preface XIII
ListofContributors XV
1 Introduction:AntibodyStructureandFunction 1
ArvindRajpal,PavelStrop,YikAndyYeung,andJavierChaparro-Riggers,
andJaumePons
1.1 IntroductiontoAntibodies 1
1.2 GeneralDomainandStructureofIgG 6
1.2.1 StructuralAspectsImportantforFcFusion(s) 6
1.2.1.1 FcProtein–ProteinInteractions 6
1.2.1.2 FcGlycosylation 8
1.2.1.3 HingeandInterchainDisulfideBonds 8
1.3 TheNeonatalFcReceptor 9
1.3.1 FcRnFunctionandExpression 9
1.3.2 SpeciesDifferenceinFcRn 13
1.3.3 EngineeringtoModulatePharmacokinetics 14
1.3.3.1 FcEngineering 14
1.3.3.2 OtherEngineeringEffortstoModifyPKofanIgGor
FcFusion 15
1.4 IntroductiontoFcgR-andComplement-MediatedEffector
Functions 16
1.4.1 CellLysisandPhagocytosisMediation 17
1.4.2 FcgR-MediatedEffectorFunctions 17
1.4.2.1 FcgRBiology 17
1.4.2.2 ExpressionProfiles 18
1.4.2.3 TherapeuticRelevancy 19
1.4.3 Complement 20
1.4.3.1 C1qBiology 20
1.4.3.2 TherapeuticRelevancy 20
1.4.4 ModifyingEffectorFunctions 21
1.4.4.1 FcgR-DependentEffectorFunction 21
1.4.4.2 Engineering 22
1.4.4.3 Glycoengineering 22
VIjContents
1.4.4.4 ReducingandSilencingEffectorFunction 23
1.5 CurrentTrendsinAntibodyEngineering 25
1.5.1 Bispecific 25
1.5.2 DrugConjugates 26
References 28
PartOne MethodsofProductionforFc-FusionProteins 45
2 Fc-FusionProteinExpressionTechnology 47
JodyD.Berry,CatherineYang,JaneanFisher,EllaMendoza,
ShaniqueYoung,andDwayneStupack
2.1 Introduction 47
2.2 ExpressionSystemsUsedforFc-FusionProteins 50
2.2.1 ExpressionUsingMammalianCellLines 50
2.2.1.1 HostCells 51
2.2.1.2 CodonOptimization 52
2.2.1.3 Vectors 52
2.2.1.4 StableversusTransientExpression 53
2.2.1.5 ViralTransductionandTransfectionMethods 55
2.2.2 ExpressionUsingProkaryoticCells 57
2.2.2.1 Vectors 59
2.2.3 ExpressionUsingBaculovirus/InsectCells 60
2.2.3.1 HostCells 61
2.2.3.2 Vectors 61
2.2.3.3 AdditionalConsiderations 62
2.3 Summary 62
References 62
3 CellCulture-BasedProduction 67
Yao-MingHuang,RashmiKshirsagar,andBarbaraWoppmann,
andThomasRyll
3.1 Introduction 67
3.2 BasicAspectsofIndustrialCellCulture 69
3.2.1 TheCentralRoleoftheProductionCellLine 69
3.2.2 ProductionSystems 70
3.2.3 ProductionMode:Fed-BatchorPerfusion? 71
3.2.4 Scale-Up 73
3.2.5 RawMaterialsandProcessControl 74
3.2.6 HowtoDeveloporOptimizeaCultureProductionProcess
forFc-FusionMolecules 74
3.3 SpecificProcessConsiderationsforFc-FusionMolecules 77
3.3.1 ProductQualityChallenges 77
3.3.2 ProcessStrategiesandProcessParameters 78
3.3.2.1 TemperatureandMisfolding 78
ContentsjVII
3.3.2.2 OtherProcessParameters 79
3.3.2.3 Glycosylation 81
3.4 CaseStudies 82
3.4.1 LTBr-Fc(Baminercept) 82
3.4.2 rFVIIIFc 85
3.5 Conclusions 87
References 87
4 DownstreamProcessingofFc-FusionProteins 97
AbhinavA.ShuklaandUweGottschalk
4.1 IntroductionandOverviewofFc-FusionProteins 97
4.2 BiochemistryofFc-FusionProteins 99
4.3 PurificationofFc-FusionProteinsfromMammalianCells 100
4.3.1 PlatformApproachesforDownstreamPurification 100
4.3.2 ComparisonofProteinAChromatography,ViralInactivation,and
PolishingSteps 103
4.4 PurificationofFc-FusionProteinfromMicrobialSystems 107
4.5 FutureInnovationsinFc-FusionProteinDownstream
Processing 109
4.6 Conclusions 110
References 111
5 Formulation,DrugProduct,andDelivery:Considerations
forFc-FusionProteins 115
WenjinCao,DeirdreMurphyPiedmonte,andMargaretSpeedRicci,
andPingY.Yeh
5.1 ChallengesofMoleculeDesignandProteinFormulation 115
5.2 ThePromiseofFc-FusionProteins 116
5.3 CurrentLandscapeofCommercialAntibody-Related
Products 118
5.4 FcConjugatesComparedtomAbCounterparts 118
5.5 FactorsinSelectingLiquidversusLyophilizedFormulations 126
5.6 AdvantagesandDisadvantagesofaLyophilizedProduct 126
5.7 TheGeneralLyophilizationFormulationStrategyforFc-Fusion
Proteins 127
5.7.1 pHandBuffer 128
5.7.2 StabilizingAgents(CryoprotectantandLyoprotectant) 129
5.8 BulkingAgent 132
5.9 Surfactant 134
5.10 TheImpactofResidualMoisture 135
5.11 PracticalConsiderationsforLow-Protein-ConcentrationLyophilized
Products 138
5.12 DrugDeliveryConsiderations 139
5.13 DeviceConsiderations 141
5.14 AssessingFeasibilityofaMultidoseFormulation 142
VIIIjContents
5.15 OverageConsiderations 142
5.16 Summary 143
References 144
6 QualitybyDesignAppliedtoaFc-FusionProtein:ACaseStudy 155
AlexEon-Duval,RalfGleixner,PascalValax,MiroslavSoos,
BenjaminNeunstoecklin,MassimoMorbidelli,andHerv(cid:1)eBroly
6.1 Introduction 155
6.1.1 Atacicept:ANovelImmunomodulatorwithBCellTargeting
Properties 155
6.1.2 MolecularCharacteristics 155
6.1.3 QualitybyDesignConcept 157
6.2 CriticalQualityAttributes 159
6.3 CriticalProcessParameters 160
6.4 ProcessCharacterization 161
6.5 GlobalMultistepDesignSpace 164
6.6 RobustnessStudies 168
6.7 AdaptiveStrategy 169
6.8 EngineeringDesignSpace 171
6.8.1 PrincipleoftheEngineeringDesignSpace 171
6.8.2 TheShearStressasOneElementoftheEngineering
DesignSpace 173
6.9 ControlStrategy 176
6.9.1 ProcessControls 177
6.9.2 TestingControls 177
6.9.3 ProcessMonitoring 179
6.9.4 MaterialControl 179
6.10 ContinuousProcessVerification 180
6.11 ExpandedChangeProtocolandContinualImprovement 182
6.12 BusinessCase 183
References 187
7 AnalyticalMethodsUsedtoCharacterizeFc-FusionProteins 191
EsoheIdusogieandMichaelMulkerrin
7.1 Background 191
7.2 ProductCharacterization 193
7.2.1 PhysiochemicalAnalysis 195
7.2.1.1 MeasurementofStrengthbyAbsorbanceat280nm 195
7.2.1.2 DeterminationofIdentityandEvaluationofChargeVariants 195
7.2.1.3 MeasurementofPurityandIntegrity 198
7.2.1.4 MassAnalysisandConfirmationofPrimaryStructure 198
7.2.1.5 OligosaccharideAnalysis 199
7.2.1.6 Purity(Product-RelatedVariants) 200
7.2.2 MeasurementofPotency 201
7.2.3 Process-RelatedImpuritiesandContaminants 204