Modern Biopharmaceuticals

2013 Pages·2003·29.48 MB·English

by  Gary Walsh

Jörg Knäblein(Ed.)
ModernBiopharmaceuticals
ModernBiopharmaceuticals.EditedbyJ.Knäblein
Copyright©2005WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:3-527-31184-X
Further Titles of Interest
GaryWalsh OliverKayser,RainerH.Müller(Eds.)
Biopharmaceuticals Pharmaceutical Biotechnology
Biochemistry andBiotechnology DrugDiscovery andClinical Applications
2003 2004
ISBN0-470-84326-8 ISBN3-527-30554-8
GaryWalsh RainerFischer,StefanSchillberg(Eds.)
Proteins Molecular Farming
Biochemistry andBiotechnology Plant-madePharmaceuticals andTechnical
Proteins
2001
ISBN0-471-89907-0 2004
ISBN3-527-30786-9
RodneyJ.Y.Ho,MiloGibaldi
Biotechnology MartinSchleef(Ed.)
and Biopharmaceuticals DNA-Pharmaceuticals
Transforming ProteinsandGenesinto Drugs Formulation andDelivery inGeneTherapy
andDNAVaccination
2003
ISBN0-471-20690-3 2005
ISBN3-527-31187-4
Chi-HueyWong(Ed.)
Carbohydrate-based RolfD.Schmid,RuthHammelehle
Drug Discovery Pocket Guide to Biotechnology
and Genetic Engineering
2003
ISBN3-527-30632-3 2003
ISBN3-527-30895-4
Modern Biopharmaceuticals
Volume
Design, Development and Optimization
Edited by
Jörg Knäblein
Editor (cid:1) All books published by Wiley-VCH are carefully pro-
duced.Nevertheless,authors,editors,andpublisherdo
Dr.JörgKnäblein notwarranttheinformationcontainedinthesebooks,
HeadMicrobiologicalChemistry includingthisbook,tobefreeoferrors.Readersare
ScheringAG advisedtokeepinmindthatstatements,data,illustrati-
Müllerstraße178 ons,proceduraldetailsorotheritemsmayinadvertently
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©2005WILEY-VCHVerlagGmbH&Co.KGaA,
Weinheim
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otherlanguages).Nopartofthisbookmayberepro-
ducedinanyform–nortransmittedortranslatedinto
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PrintedintheFederalRepublicofGermany
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ISBN-13 978-3-527-31184-2
ISBN-10 3-527-31184-X
V
Contents
Volume 1
Prologue XXV
Dedication XXIX
Foreword XXXI
Foreword XXXV
Quotes XXXVII
Executive Summary XLI
ListofContributors CXXIII
Introduction
CurrentStatusofBiopharmaceuticals: Approved ProductsandTrendsinApprovals 1
Gary Walsh
1 What areBiopharmaceuticals? 2
2 A Global Snapshot 2
3 Upstream and Downstream Processing 3
4 Trendsin Approvals 6
5 Declining Number ofApprovals 8
6 Products ApprovedforHuman Use 9
7 Products ApprovedforVeterinary Use 25
8 Likely Future Directions 27
9 Concluding Remarks 33
ModernBiopharmaceuticals.EditedbyJ.Knäblein
Copyright©2005WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:3-527-31184-X
VI Contents
PartI Biopharmaceuticals UsedinMolecularMedicine
FromGenometoClinic–CorrelationBetweenGenes,DiseasesandBiopharmaceuticals 37
1 BeginningtoUnderstandtheEndoftheChromosome 37
ThomasR.Cech
1.1 Introduction 37
1.2 TelomereTerminal Transferase 38
1.3 TelomeraseContainsan Essential RNA 38
1.4 Finally, the Protein:TelomeraseReverseTranscriptase 39
1.5 Current Picture ofTelomerase 40
1.6 Regulation ofTelomerase 42
1.7 Cellular Immortality 44
1.8 Cancer 44
2 TheRoleofPharmacogenetics/Pharmacogenomics
inDrugDevelopment andRegulatory Review:CurrentStatus 49
Shiew-MeiHuangandLawrence J. Lesko
2.1 Introduction 50
2.2 Variability in Drug Response 50
2.3 Drug-metabolizing Enzymes and Transporters 52
2.4 Applications ofPharmacogenetics and Pharmacogenomics in Drug Development
and Regulatory Review 54
2.5 Determinationof DifferentGenotype GroupsbasedonKnown Valid
and ProbableValid Biomarkers 56
2.6 Drug Interactions 60
2.7 Voluntary versusRequiredSubmissions 60
2.8 Labeling Implications 63
2.9 Conclusion 64
3 Large-scaleDetection ofGeneticVariation:TheKeytoPersonalizedMedicine 71
Joerg GeistlingerandPeter Ahnert
3.1 Genetic Variation,DiseaseSusceptibility and Drug Response 73
3.2 Pharmacogenetics and Pharmacogenomics 74
3.3 PersonalizedMedicine 76
3.4 SNPs in Clinical Applications 78
3.5 Strategies in SNP Discovery 80
3.6 SNP Technologies 83
3.7 Polydimensional SNP-Chips: The Array-On Technology 88
3.8 Outlook 93
4 ASystemsBiology ApproachtoTargetIdentification andValidation
forHumanChronicDiseaseDrugDiscovery 99
BonnieE. GouldRothberg,CarolE.A. Pen˜a,andJonathanM.Rothberg
4.1 Limitations in the ChronicDiseaseDrug DiscoveryProcess 100
Contents VII
4.2 Creating the Pharmaceutically TractableGenome 104
4.3 Integrated Systems Biology Approachesto Drug Target Validation forSpecific
Clinical Indications 110
4.4 Conclusion 123
5 TheDevelopment ofHerceptin®:
PavingtheWayforIndividualizedCancerTherapy 127
ThorstenS.GutjahrandCarstenReinhardt
5.1 Introduction 128
5.2 HER2 129
5.3 Herceptin Mechanism ofAction and Effectson Cellular Processes 130
5.4 Preclinical Evidence 131
5.5 HER2 Testing as a Prerequisitefor HerceptinTherapy: Development
ofCommercially Availableand Validated Testing Methodologies 133
5.6 HER2 Testing Algorithm 135
5.7 Herceptin in Clinical Use 136
5.8 Future Prospectsfor Herceptinand other Targeted Therapies 143
5.9 Herceptin in Early Breast Cancer 143
5.10 Herceptin Adjuvant Trials 143
5.11 Conclusion 145
siRNA–theMagicBulletandOtherGeneTherapeutical Approaches 151
6 Adenovirus-basedGeneTherapy:TherapeuticAngiogenesis
withAdenovirus5Fibroblast GrowthFactor-4(Ad5FGF-4)inPatients
withChronicMyocardial Ischemia 151
MichaelMcCaman,FranciscoJ. Castillo,FarahFawaz,YasushiOgawa,Erik Whiteley,
ElisabethLehmberg, MeiTan,Jacob Kung,Bruce Mann,Erno PungorJr.,
andGabor M.Rubanyi
6.1 Introduction 152
6.2 Therapeutic Angiogenesisand the Importance ofCollateral Vessels 153
6.3 Designing an Intervention Suitable forTherapeutic Angiogenesis 153
6.4 Production and Characterization ofthe Ad5FGF-4 Vector 156
6.5 Pre-clinical Efficacy and Safety ofAd5FGF-4 in Pigs 172
6.6 Clinical Studies 175
6.7 Summary and Conclusions 178
7 MIDGEVectorsanddSLIMImmunomodulators:
DNA-basedMoleculesforGeneTherapeuticStrategies 183
ManuelSchmidt,Barbara Volz,andBurghardtWittig
7.1 VectorsforGeneTherapy 184
7.2 Immunomodulatory Molecules 193
7.3 Application of MIDGE Vectorsand dSLIM Immunomodulators 198
VIII Contents
8 Nonprotein-coding RNAsandtheirPotentialasBiopharmaceuticals 213
Maciej Szymanski,JanBarciszewskiandVolker A. Erdmann
8.1 Introduction 213
8.2 The Contents ofthe Genomes 214
8.3 npcRNAs 215
8.4 FunctionsofnpcRNAs 217
8.5 npcRNAs and Human Diseases 219
8.6 miRNAs 222
8.7 Future Prospects 223
9 Double-strandedDecoyOligonucleotides asnewBiopharmaceuticals 229
AndreasH. WagnerandHeiko E. von der Leyen
9.1 Introduction 230
9.2 Therapeutic DecoyODN Application 232
10 RationalsiRNADesignforRNAInterference:
Optimizations forTherapeuticUseandCurrentApplications 243
AnastasiaKhvorova, QuetaBoese, andWilliamS. Marshall
10.1 RNAi: Historyand Mechanism 244
10.2 Early siRNA Design Parameters 248
10.3 Current siRNA Design Considerations 251
10.4 Therapeutic Applications ofRNAi 259
10.5 Summary: The Future ofRNAi in Biopharmaceutical Development 264
MobilisinMobile–HumanEmbryonicStemCellsandOtherSourcesforCellTherapy 269
11 TheFirstClonedHumanEmbryo:AnUnlimitedSourceofStemCells
forTherapeuticCloning 269
Woo SukHwang,Byeong ChunLee, SungKeun Kang,andShinYongMoon
11.1 Introduction 270
11.2 Human Somatic Cell Nuclear Transfer(SCNT) 270
11.3 Establishment and Characterization of Human SCNT ES Cells 276
11.4 Reprogramming Adult Cells into an Embryonic State 277
11.5 Discussionand Conclusion 279
12 Myocardial RegenerationStrategies usingHumanEmbryonic StemCells 283
IzhakKehat,Oren Caspi,andLior Gepstein
12.1 Introduction 284
12.2 Derivationof Human Embryonic Stem Cells 286
12.3 Cardiomyocyte Differentiationof ES Cells 289
12.4 PossibleResearchand Clinical Applications ofthe hES-derived
Cardiomyocytes 293
12.5 Early Cardiac Lineage Differentiation 293
12.6 Myocardial RegenerationStrategies using hES-derivedCardiomyocytes 295
Contents IX
12.7 Functional Integration ofthe Cell Grafts 296
12.8 Cardiomyocyte Enrichment, Purification,and Up-scaling Strategies 298
12.9 Preventionof Immunological Rejection 299
12.10 Conclusions 300
13 GeneandCell-basedTherapiesforCardiovascular Disease 305
Abeel A. Mangi
13.1 Introduction 306
13.2 Gene Therapy as Novel Drug Delivery 306
13.3 Cell-basedGene Therapy and Regenerative CardiovascularMedicine 319
13.4 Future Directionsand Challenges 321
14 Spheramine®:ACellTherapeuticApproachtoParkinson’sDisease 325
Elke Reissig,Hermann Graf, andFriedrich-JoachimKapp
14.1 Introduction 326
14.2 PD 326
14.3 Spheramine 334
14.4 Randomized,Double-blind,Placebo-controlledMulticenter Study of the Safety,
Tolerability and EfficacyofSpheramine Implanted Bilaterally
into the PostcommissuralPutamen ofPatients with AdvancedPD 343
14.5 Summary and Outlook 348
15 Applying HumanCellstoOrganogenesisandTransplantation 353
BenjaminDekel andYairReisner
15.1 Growing Demands forKidney Allograft Transplantation 354
15.2 Alternative SourcesforHuman Renal Allografts 354
15.3 Conclusions 367
Volume 2
PartII Biopharmaceuticals andTheirModeofAction
QuidproQuo–Lysisvs.Coagulation intheFine-tunedBalance oftheClotting Cascade 377
1 MechanismsofSerineProteinaseActivation: InsightsfortheDevelopment
ofBiopharmaceuticals forCoagulation andFibrinolysis 377
RainerFriedrich
1.1 Introduction 378
1.2 Bacterial Activatorsof HostZymogens 381
1.3 Some Remarkson Nonproteolytic Activators 388
2 Application ofthePrincipleofPolyvalency toProteaseInhibition 395
LuisMoroder
2.1 Introduction 395