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Contents  
 
Volume 1  
Prologue XXV
Dedication XXIX
Foreword XXXI
Foreword XXXV
Quotes XXXVII
Executive Summary XLI
List of Contributors CXXIII
Introduction
Current Status of Biopharmaceuticals: Approved Products and Trends in Approvals
Gary Walsh 		1
1 What are Biopharmaceuticals? 2
2 A Global Snapshot 2
3 Upstream and Downstream Processing 3
4 Trends in Approvals 6
5 Declining Number of Approvals 8
6 Products Approved for Human Use 9
7 Products Approved for Veterinary Use 25
8 Likely Future Directions 27
9 Concluding Remarks 33
Part I Biopharmaceuticals Used in Molecular Medicine  
From Genome to Clinic -- Correlation Between Genes, Diseases and Biopharmaceuticals 37
1 Beginning to Understand the End of the Chromosome
Thomas R.Cech 		37
1.1 Introduction 37
1.2 Telomere Terminal Transferase 38
1.3 Telomerase Contains an Essential RNA 38
1.4 Finally, the Protein: Telomerase Reverse Transcriptase 39
1.5 Current Picture of Telomerase 40
1.6 Regulation of Telomerase 42
1.7 Cellular Immortality 44
1.8 Cancer 44
2 The Role of Pharmacogenetics/Pharmacogenomics in Drug Development and Regulatory Review: Current Status
Shiew-Mei Huang and Lawrence J. Lesko 		49
2.1 Introduction 50
2.2 Variability in Drug Response 50
2.3 Drug-metabolizing Enzymes and Transporters 52
2.4 Applications of Pharmacogenetics and Pharmacogenomics in Drug Development and Regulatory Review 54
2.5 Determination of Different Genotype Groups based on Known Valid and Probable Valid Biomarkers 56
2.6 Drug Interactions 60
2.7 Voluntary versus Required Submissions 60
2.8 Labeling Implications 63
2.9 Conclusion 64
3 Large-scale Detection of Genetic Variation: The Key to Personalized Medicine
Joerg Geistlinger and Peter Ahnert 		71
3.1 Genetic Variation, Disease Susceptibility and Drug Response 73
3.2 Pharmacogenetics and Pharmacogenomics 74
3.3 Personalized Medicine 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 A Systems Biology Approach to Target Identification and Validation for Human Chronic Disease Drug Discovery
Bonnie E. Gould Rothberg, Carol E.A. Pen a, and Jonathan M. Rothberg 		99
4.1 Limitations in the Chronic Disease Drug Discovery Process 100
4.2 Creating the Pharmaceutically Tractable Genome 104
4.3 Integrated Systems Biology Approaches to Drug Target Validation for Specific Clinical Indications 110
4.4 Conclusion 123
5 The Development of Herceptin(R): Paving the Way for Individualized Cancer Therapy
Thorsten S. Gutjahr and Carsten Reinhardt 		127
5.1 Introduction 128
5.2 HER2 129
5.3 Herceptin Mechanism of Action and Effects on Cellular Processes 130
5.4 Preclinical Evidence 131
5.5 HER2 Testing as a Prerequisite for Herceptin Therapy: Development of Commercially Available and Validated Testing Methodologies 133
5.6 HER2 Testing Algorithm 135
5.7 Herceptin in Clinical Use 136
5.8 Future Prospects for Herceptin and other Targeted Therapies 143
5.9 Herceptin in Early Breast Cancer 143
5.10 Herceptin Adjuvant Trials 143
5.11 Conclusion 145
siRNA -- the Magic Bullet and Other Gene Therapeutical Approaches 151
6 Adenovirus-based Gene Therapy: Therapeutic Angiogenesis with Adenovirus 5 Fibroblast Growth Factor-4 (Ad5FGF-4) in Patients with Chronic Myocardial Ischemia
Michael McCaman, Francisco J. Castillo, Farah Fawaz, Yasushi Ogawa, Erik Whiteley, Elisabeth Lehmberg, Mei Tan, Jacob Kung, Bruce Mann, Erno Pungor Jr., and Gabor M. Rubanyi 		151
6.1 Introduction 152
6.2 Therapeutic Angiogenesis and the Importance of Collateral Vessels 153
6.3 Designing an Intervention Suitable for Therapeutic Angiogenesis 153
6.4 Production and Characterization of the Ad5FGF-4 Vector 156
6.5 Pre-clinical Efficacy and Safety of Ad5FGF-4 in Pigs 172
6.6 Clinical Studies 175
6.7 Summary and Conclusions 178
7 MIDGE Vectors and dSLIM Immunomodulators: DNA-based Molecules for Gene Therapeutic Strategies
Manuel Schmidt, Barbara Volz, and Burghardt Wittig 		183
7.1 Vectors for Gene Therapy 184
7.2 Immunomodulatory Molecules 193
7.3 Application of MIDGE Vectors and dSLIM Immunomodulators 198
8 Nonprotein-coding RNAs and their Potential as Biopharmaceuticals
Maciej Szymanski, Jan Barciszewski and Volker A. Erdmann 		213
8.1 Introduction 213
8.2 The Contents of the Genomes 214
8.3 npcRNAs 215
8.4 Functions of npcRNAs 217
8.5 npcRNAs and Human Diseases 219
8.6 miRNAs 222
8.7 Future Prospects 223
9 Double-stranded Decoy Oligonucleotides as new Biopharmaceuticals
Andreas H. Wagner and Heiko E. von der Leyen 		229
9.1 Introduction 230
9.2 Therapeutic Decoy ODN Application 232
10 Rational siRNA Design for RNA Interference: Optimizations for Therapeutic Use and Current Applications
Anastasia Khvorova, Queta Boese, and William S. Marshall 		243
10.1 RNAi: History and Mechanism 244
10.2 Early siRNA Design Parameters 248
10.3 Current siRNA Design Considerations 251
10.4 Therapeutic Applications of RNAi 259
10.5 Summary: The Future of RNAi in Biopharmaceutical Development 264
Mobilis in Mobile -- Human Embryonic Stem Cells and Other Sources for Cell Therapy 269
11 The First Cloned Human Embryo: An Unlimited Source of Stem Cells for Therapeutic Cloning
Woo Suk Hwang, Byeong Chun Lee, Sung Keun Kang, and Shin Yong Moon 		269
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 Discussion and Conclusion 279
12 Myocardial Regeneration Strategies using Human Embryonic Stem Cells
Izhak Kehat, Oren Caspi, and Lior Gepstein 		283
12.1 Introduction 284
12.2 Derivation of Human Embryonic Stem Cells 286
12.3 Cardiomyocyte Differentiation of ES Cells 289
12.4 Possible Research and Clinical Applications of the hES-derived Cardiomyocytes 293
12.5 Early Cardiac Lineage Differentiation 293
12.6 Myocardial Regeneration Strategies using hES-derived Cardiomyocytes 295
12.7 Functional Integration of the Cell Grafts 296
12.8 Cardiomyocyte Enrichment, Purification, and Up-scaling Strategies 298
12.9 Prevention of Immunological Rejection 299
12.10 Conclusions 300
13 Gene and Cell-based Therapies for Cardiovascular Disease
Abeel A. Mangi 		305
13.1 Introduction 306
13.2 Gene Therapy as Novel Drug Delivery 306
13.3 Cell-based Gene Therapy and Regenerative Cardiovascular Medicine 319
13.4 Future Directions and Challenges 321
14 Spheramine(R): A Cell Therapeutic Approach to Parkinsons Disease
Elke Reissig, Hermann Graf, and Friedrich-Joachim Kapp 		325
14.1 Introduction 326
14.2 PD 326
14.3 Spheramine 334
14.4 Randomized, Double-blind, Placebo-controlled Multicenter Study of the Safety, Tolerability and Efficacy of Spheramine Implanted Bilaterally into the Postcommissural Putamen of Patients with Advanced PD 343
14.5 Summary and Outlook 348
15 Applying Human Cells to Organogenesis and Transplantation
Benjamin Dekel and Yair Reisner 		353
15.1 Growing Demands for Kidney Allograft Transplantation 354
15.2 Alternative Sources for Human Renal Allografts 354
15.3 Conclusions 367
Volume 2  
Part II Biopharmaceuticals and Their Mode of Action
Quid pro Quo -- Lysis vs. Coagulation in the Fine-tuned Balance of the Clotting Cascade 377
1 Mechanisms of Serine Proteinase Activation: Insights for the Development of Biopharmaceuticals for Coagulation and Fibrinolysis
Rainer Friedrich 		377
1.1 Introduction 378
1.2 Bacterial Activators of Host Zymogens 381
1.3 Some Remarks on Nonproteolytic Activators 388
2 Application of the Principle of Polyvalency to Protease Inhibition
Luis Moroder 		395
2.1 Introduction 395
2.2 Thermodynamic Model of Bivalent Ligand Binding 396
2.3 Homo- and Heterobivalent Inhibitors of the Yeast 20S Proteasome 398
2.4 Bivalent Inhibition of Mast Cell b-Tryptase 405
2.5 Heterobivalent Inhibition of Thrombin 411
2.6 Perspectives 414
3 A New Technology Standard for Safety and Efficacy in Factor VIII Replacement Therapy: Designing an Advanced Category rFVIII Concentrate
Norbert Riedel and Friedrich Dorner 		419
3.1 Introduction 420
3.2 Development of rFVIII 428
3.3 Production of rFVIII 430
3.4 Pathogen Safety 433
3.5 Quality Control 435
3.6 Purity and Potency 435
3.7 Preclinical Studies 436
3.8 Clinical Studies 439
3.9 Summary 447
Errare Humanum Est -- What Causes Cancer and How to Selectively Fight Tumors 451
4 Biopharmaceutical Drugs from Natural Sources
David J. Newman, Gordon M. Cragg, and Barry R. O'Keefe 		451
4.1 Biotechnologically Produced Proteins and Peptides as Approved Drugs 452
4.2 Potential Agents from Non-mammalian Sources as Leads to Novel Therapies 481
4.3 Overall Concluding Comments 488
5 Biopharmaceuticals as Targeting Vehicles for In situ Radiotherapy of Malignancies
Raymond M. Reilly 		497
5.1 Introduction 498
5.2 Principles of Targeted In situ Radiotherapy of Malignancies 499
5.3 RIT of Non-Hodgkin's B-Cell Lymphomas: The Pre-eminent Success Story 500
5.4 Other Strategies for In situ Radiotherapy of Non-Hodgkin's Lymphoma 505
5.5 Radioimmunotherapy of AML: Success but not Cure 505
5.6 RIT of Solid Tumors: Encouraging Results n Minimal Residual Disease 507
5.7 Pre-Targeting Strategies: Improving the Therapeutic Index of RIT 511
5.8 Peptide-Directed In situ Radiotherapy: Targeting Somatostatin Receptors 516
5.9 Auger Electron Radiotherapy: Anti-tumor Effects at the Single Cell Level 519
5.10 -Particle RIT: Anti-tumor Effects at the Multi-cell Level 525
5.11 Conclusion 526
6 New Directions in Tumor Therapy -- Amino Acid Deptetion with GlutaDON(R) as Treatment for Cancer
Rolf Kalhammer and Natarajan Sethuraman 		537
6.1 Rationale for GlutaDON(R) Therapy 537
6.2 Preclinical Studies 539
6.3 PEGylation and Protection from Inactivation 541
6.4 Toxicology 545
6.5 Clinical Trial 545
6.6 Summary and Conclusions 546
Mundus Vult Decipi -- High Mutation Rates of HIV and New Paradigms for Treatment 549
7 AIDS Gene Therapy: A Vector Selectively Able to Destroy Latently HIV-1-infected Cells
Francisco Luque Vzquez and Ricardo Oya 		549
7.1 The Genes and Life Cycle of HIV-1 551
7.2 Gene Therapy of AIDS 553
7.3 Viral Latency: the Real Challenge 557
7.4 A Vector Able Selectively to Destroy Latently Infected Cells 559
8 Combinatorial RNA-based Therapies for HIV-1
Kevin V. Morris and John J. Rossi 		569
8.1 Introduction 569
8.2 RNA-based Antiviral Agents 570
8.3 RNAi: Diversity of Viral Targets 571
8.4 Delivery of siRNAs to Target Cells 573
8.5 Challenges for RNA-based Therapies 577
8.6 Summary and Conclusion 577
Part III Improving the Development of Biopharmaceuticals  
Citius, Altius, Fortius -- Acceleration by High Throughput and Ultra-HT 583
1 Design of Modern Biopharmaceuticals by Ultra-high-throughput Screening and Directed Evolution
Markus Rarbach, Wayne M. Coco, Andre Koltermann, Ulrich Kettling, and Manfred Eigen 		583
1.1 Modern Biopharmaceuticals 584
1.2 Directed Evolution Fundamentals 585
1.3 Generation of Protein Diversity 586
1.4 Selection Strategies 593
1.5 High-throughput and High-content Screening of Protein Libraries 594
1.6 Directed Evolution of Biopharmaceuticals 598
1.7 Conclusions 601
2 Learning from Viruses: High-throughput Cloning using the Gateway System to Transfer Genes without Restriction Enzymes
Jonathan D. Chesnut 		605
2.1 Introduction 605
2.2 Background 606
2.3 Engineering the Lambda System to Create Gateway 609
2.4 The Gateway Reactions 610
2.5 Creating Gateway Entry Clones 611
2.6 Gateway Destination Vectors 613
2.7 Applications Enabled by Gateway Cloning 614
2.8 HTP Expression Analysis in Mammalian Cells 614
2.9 HTP Cloning and Expression in a Baculovirus System 615
2.10 Multisite Gateway 616
2.11 Creation of Entry Vectors and Three-fragment Multisite Assembly Reaction 618
2.12 Perspective 621
In Vivo Veritas -- Early Target Validation in Knock-out Mice and More 621
3 Target Validation: An Important Early Step in the Development of Novel Biopharmaceuticals in the Post-genomic Era
Christoph P. Bagowski 		621
3.1 Introduction 622
3.2 RNA- and DNA-based Techniques for Post-transcriptional Regulation of Molecular Targets, and their Potential as Biopharmaceutical Drugs 624
3.3 Peptide and Protein-based Approaches 636
3.4 Protein Kinases as Targets for Drug Development 639
3.5 Cell-based Assays for In vitro Target Validation„ in the Drug Discovery Process 640
3.6 Animal Models as the Ultimate Target Validation 645
3.7 Summary and Conclusions 645
4 Genetically Modified Mice in Medical and Pharmaceutical Research
Cord Brakebusch 		649
4.1 Disease-oriented Research in Genetically Modified Mice 649
4.2 Generation of Genetically Modified Mice by Gene Targeting 651
4.3 Analysis of Genetically Modified Mice 659
4.4 Alternative Methods 659
5 An NIH Model Organism for Biopharmaceutical and Biomedical Research: The Lower Eukaryote Dictyostelium discoideum
Thomas Winckler, Ilse Zündorf, and Theodor Dingermann 		661
5.1 Introduction 664
5.2 The Gene Discovery Tool Box or Dictyostelium Research 665
5.3 Production of Recombinant Proteins in D. discoideum 672
5.4 Dictyostelium dis„coide„um in Biomedical Research 685
5.5 Conclusions 689
Revolution by Evolution -- Rational Design for Desire and Scientific Art of Optimization 695
6 Releasing the Spring: Cofactor- and Substrate-assisted Activation of Factor IXa
Hans Brandstetter and Katrin Sichler 		695
6.1 Introduction 695
6.2 The Zymogen Form of fIX is Fully Inactive 697
6.3 Relevance of Tyr99 on the Stability of the 99-loop 697
6.4 Lys98 Hinders Substrate Binding to fIXa both Sterically and Electrostatically 698
6.5 Tyr177 Locks the 99-loop in an Inactive Conformation, which is Released by Cofactor fVIIIa and Modified by the Physiologic Substrate fX 699
6.6 S1 Site Mutations Decrease the Activity of fIXa 699
6.7 Evolutionary Relation of fIXa and fXa is Reflected in the Dependence of Activity Changes on Arg/Lys Substrates 700
6.8 By Binding at the 60-loop Ethylene Glycol Indirectly Reorganizes the 99-loop and Allosterically Stimulates the Activity of fIXa 700
6.9 Summary and Conclusion 701
7 Accelerating Diagnostic Product Development Process with Molecular Rational Design and Directed Evolution
Harald Sobek, Rainer Schmuck, and Zhixin Shao 		703
7.1 Introduction 704
7.2 Strategies for Optimizing Diagnostic Proteins 705
7.3 Examples 709
7.4 Summary 717
Volume 3  
Part IV Production of Biopharmaceuticals  
The Industry's Workhorses -- Mammalian Expression Systems 723
1 Manufacture of Recombinant Biopharmaceutical Proteins by Cultivated Mammalian Cells in Bioreactors
Florian M. Wurm 		723
1.1 Introduction 724
1.2 Vectors, Transfections, and Cell Line Generation 727
1.3 Host Cell Engineering 731
1.4 Gene Transfer and Gene Amplification in Mammalian Cells 733
1.5 Production Principles for Mammalian Cells: Anchorage-dependent Cultures and Suspension Cultures 737
1.6 Large-scale Transient Expression 744
1.7 Regulatory Issues 745
1.8 Concluding Remarks 751
2 Alternative Strategies and New Cell Lines for High-level Production of Biopharmaceuticals
Thomas Rose, Karsten Winkler, Elisabeth Brundke, Ingo Jordan and Volker Sandig 		761
2.1 Mammalian Cells as a Workhorse to Produce Protein-based Biopharmaceuticals 761
2.2 The Cell Line of Choice 762
2.3 Pushing Expression Levels Impact of Vector Design and Cell Clone Selection 764
2.4 A Single CHO High-producer Clone for Multiple Products 766
2.5 The G-line: Use of the Immunoglobulin Locus of a Human/Mouse Heterohybridoma for Heterologous Gene Expression 769
2.6 Human Designer Cell Lines 774
2.7 Summary and Conclusion 776
3 PER.C6(R) Cells for the Manufacture of Biopharmaceutical Proteins
Chris Yallop, John Crowley, Johanne Cote, Kirsten Hegmans-Brouwer, Fija Lagerwerf, Rodney Gagne, Jose Coco Martin, Nico Oosterhuis, Dirk-Jan Opstelten, and Abraham Bout 		779
3.1 Introduction 780
3.2 Generation of PER.C6 Cells 782
3.3 PER.C6 Cells for the Manufacture of Recombinant Proteins 784
3.4 Fed-batch Process Development 789
3.5 Operation of PER.C6 Cells in Continuous Perfusion 794
3.6 Characterization of Antibodies Produced by PER.C6 Cells 797
3.7 Conclusion 803
4 Use of the Glutamine Synthetase (GS) Expression System for the Rapid Development of Highly Productive Mammalian Cell Processes
John R. Birch, David O. Mainwaring, and Andrew J. Racher 		809
4.1 Introduction 809
4.2 Cell Line Construction and Selection 810
4.3 Cell Line Stability 818
4.4 Cell Engineering to Increase Productivity 819
4.5 Selection of Useful Cell Sub-populations 822
4.6 Process Development 823
4.7 Summary 830
Vivat, Crescat, Floreat -- A Ripe and Blooming Market for Transgenic Animals and Plants 833
5 Biopharmaceuticals Derived from Transgenic Plants and Animals
Julio Baez 		833
5.1 Introduction 834
5.2 Advantages and Disadvantages of Transgenic Systems for the Production of Biopharmaceuticals 845
5.3 Commercial Biopharmaceuticals with Human Clinical Experience for Therapeutic, Immunoprophylactic, and Medical Device Use derived from Transgenic Systems 852
5.4 Conclusions 873
6 Production of Recombinant Proteins in Plants
Victor Klimyuk, Sylvestre Marillonnet, Jörg Knäblein, Michael McCaman, and Yuri Gleba 		893
6.1 Introduction 893
6.2 Plant-based Expression Systems 894
6.3 Plant-made Recombinant Proteins available Commercially, and under Development 903
6.4 Comparative Analysis of the Expression Systems and Production Platforms 907
6.5 Summary and Conclusion 909
7 Humanized Glycosylation: Production of Biopharmaceuticals in a Moss Bioreactor
Gilbert Gorr and Sabrina Wagner 		919
7.1 Introduction 919
7.2 Mosses: Some General Aspects 920
7.3 Cell Culture 922
7.4 Recombinant Expression 923
7.5 N-Glycosylation 924
7.6 Conclusions and Outlook 927
8 ExpressTec: High-level Expression of Biopharmaceuticals in Cereal Grains
Ning Huang and Daichang Yang 		931
8.1 Introduction 931
8.2 Development of ExpressTec for High-level Expression of Recombinant Proteins in Cereal Grains 932
8.3 High-level Expression of Biopharmaceuticals in Cereal Grain using ExpressTec 938
8.4 Impact of Expression Level on the Cost of Goods 945
8.5 Perspectives of Expressing Biopharmaceuticals„ in High Plants 946
9 Biopharmaceutical Production in Cultured Plant Cells
Stefan Schillberg, Richard M. Twyman, and Rainer Fischer 		949
9.1 Introduction 950
9.2 Recombinant Proteins Produced in Plant Cell Suspension Cultures 951
9.3 Challenges and Solutions for the Production of Recombinant Proteins 954
9.4 Process Engineering 958
9.5 Downstream Processing 959
9.6 Regulatory Considerations 960
9.7 Conclusions 961
10 Producing Biopharmaceuticals in the Desert: Building an Abiotic Stress Tolerance in Plants for Salt, Heat, and Drought
Shimon Gepstein, Anil Grover, and Eduardo Blumwald 		967
10.1 General Comments on Abiotic Stresses 968
10.2 Drought and Salt Tolerance 969
10.3 High-temperature Stress 981
10.4 Conclusions and Perspectives 989
11 The First Biopharmaceutical from Transgenic Animals: ATryn
Yann Echelard, Harry M. Meade, and Carol A. Ziomek 		995
11.1 Introduction 996
11.2 Recombinant Production of AT 998
11.3 Characterization of rhAT 1003
11.4 Preclinical Studies 1007
11.5 Clinical Trials with rhAT 1011
11.6 Conclusions 1016
Alea Non Iacta Est -- Improving Established Expression Systems 1021
12 Producing Modern Biopharmaceuticals: The Bayer HealthCare Pharma Experience with a Range of Expression Systems
Heiner Apeler 		1021
12.1 The Escherichia coli Expression Platform 1022
12.2 The Saccharomyces cerevisiae Expression Platform 1027
12.3 The HKB11 Expression Platform 1029
12.4 Outlook and Conclusion 1031
13 Advanced Expression of Biopharmaceuticals in Yeast at Industrial Scale: The Insulin Success Story
Asser Sloth Andersen and Ivan Diers 		1033
13.1 Introduction 1033
13.2 Design and Optimization of the Insulin Precursor Molecule 1036
13.3 Production of Insulin 1041
13.4 Conclusions and Future Aspects 1042
14 Baculovirus-based Production of Biopharmaceuticals using Insect Cell Culture Processes
Wilfried Weber and Martin Fussenegger 		1045
14.1 Introduction 1045
14.2 Molecular Tools for the Construction of Transgenic Baculoviruses 1046
14.3 Insect Cell Culture 1047
14.4 Insect Cell Glycosylation and Glycoengineering 1047
14.5 Nutrient and Kinetic Considerations for Optimized BEVS-based Protein Production 1048
14.6 Scaling-up Baculovirus-based Protein Production 1050
14.7 Generic Protocol of Optimized Protein Production 1050
14.8 Case study: Rapid Optimization of Expression Conditions and Large-scale Production of a Brutons Tyrosine Kinase Variant (BTK) 1053
14.9 Conclusion 1058
15 Robust and Cost-effective Cell-free Expression of Biopharmaceuticals: Escherichia Coli and Wheat Embryo
Luke Anthony Miles 		1063
15.1 Introduction 1064
15.2 Transcription 1066
15.3 Translational 1068
15.4 Treatment of Extracts for Synthesis of Disulfide-bonded Proteins 1072
15.5 ATP Regeneration Systems 1074
15.6 Reaction Conditions 1075
15.7 Conclusion 1079
When Success Raises its Ugly Head -- Outsourcing to Uncork the Capacity Bottleneck 1083
16 Contract Manufacturing of Biopharmaceuticals Including Antibodies or Antibody Fragments
J. Carsten Hempel and Philipp N. Hess 		1083
16.1 Introduction 1084
16.2 Expression Systems and Manufacturing Procedures 1085
16.3 Outsourcing and Contract Manufacturing 1089
16.4 Summary and Outlook 1100
Part V Biopharmaceuticals used for Diagnositics and Imaging  
From Hunter to Craftsman -- Engineering Antibodies with Nature's Universal Toolbox 1105
1 Thirty Years of Monoclonal Antibodies: A Long Way to Pharmaceutical and Commercial Success
Uwe Gottschalk and Kirsten Mundt 		1105
1.1 Introduction 1107
1.2 Making Monoclonal Antibodies 1109
1.3 Other Antibody Formats: Antibody Fragments 1113
1.4 Medical Application Areas for MAbs 1116
1.5 From Initial Failure to Success: Getting the Target Right 1117
1.6 The Market Perspective 1119
1.7 Drug Targeting: The Next Generation in Cancer Treatment 1122
1.8 Developing a Manufacturing Process for MAbs 1126
1.9 Routine Manufacture of MAbs 1127
1.10 Glycosylation and Other Post-translational Modifications 1132
1.11 Emerging Issues in MAb Production 1134
1.12 The Future of MAbs 1136
2 Modern Antibody Technology: The Impact on Drug Development
Simon Moroney and Andreas Plückthun 		1147
2.1 Introduction 1147
2.2 Immunogenicity 1148
2.3 Technology 1153
2.4 Reaching the Target: The Importance of Specificity, Affinity and Format 1163
2.5 Exerting an Effect at the Target 1168
2.6 Antibodies in their Natural Habitat: Infectious Diseases 1175
2.7 Opportunities for New Therapeutic Applications Provided by Synthetic Antibodies 1176
2.8 Future Directions and Concluding Statements 1177
3 Molecular Characterization of Autoantibody Responses in Autoimmune Diseases: Implications for Diagnosis and Understanding of Autoimmunity
Constanze Breithaupt 		1187
3.1 Autoantibodies in Autoimmune Diseases 1188
3.2 Autoantibody Epitopes 1190
3.3 Visualization of Epitopes 1195
3.4 Structural Characterization of AutoantibodyAutoantigen Complexes 1199
3.5 Conclusions 1205
Find, Fight, and Follow -- Target-specific Troika from Mother Nature's Pharmacopoiea 1211
4 Molecular Imaging and Applications for Pharmaceutical R&D
Joke G. Orsel and Tobias Schaeffter 		1211
4.1 Introduction 1212
4.2 Imaging Modalities and Contrast Agents 1213
4.3 Molecular Imaging 1225
4.4 Molecular Imaging for Drug Discovery and Development 1230
4.5 Concluding Remarks 1239
5 Design and Development of Probes for In vivo Molecular and Functional Imaging of Cancer and Cancer Therapies by Positron Emission Tomography (PET)
Eric O. Aboagye 		1243
5.1 What is Positron Emission Tomography? 1244
5.2 Radiochemistry Considerations 1246
5.3 Pharmacological Objectives in Oncology Imaging Studies 1249
5.4 The Use of Radiolabeled Drugs to Image Tumor and Normal Tissue Pharmacokinetics 1250
5.5 Pharmacodynamic Studies 1254
5.6 Conclusions 1264
6 Ligand-based Targeting of Disease: From Antibodies to Small Organic (Synthetic) Ligands
Michela Silacci and Dario Neri 		1271
6.1 Introduction 1272
6.2 Ligands 1273
6.3 Classes of Diseases 1276
6.4 From a Ligand to a Product 1288
6.5 Concluding Remarks 1289
7 Ultrasound Theranostics: Antibody-based Microbubble Conjugates as Targeted In vivo Contrast Agents and Advanced Drug Delivery Systems
Andreas Briel, Michael Reinhardt, Mathias Mäurer, and Peter Hauff 		1301
7.1 Motivation: ´´Find, Fight and Follow!´´ 1302
7.2 Ultrasound: ´´Hear the Symptoms´´ 1304
7.3 Ultrasound Contrast: ´´Tiny Bubbles´´ 1305
7.4 The Perfect Modality: ´´Sensitive Particle Acoustic Quantification (SPAQ)´´ 1308
7.5 Targeting and Molecular Imaging: ´´The Sound of an Antibody´´ 1309
7.6 Drug Delivery: ´´The Magic Bullet´´ 1315
7.7 Ultrasound, Microbubbles and Gene Delivery: ´´Noninvasive Micro-Gene Guns´´ 1318
7.8 Summary: Ultrasound Theranostics ´´Building a Bridge between Therapy and Diagnosis´´ 1320
Getting Insight -- Sense the Urgency for Early Diagnostics 1325
8 Development of Multi-marker-based Diagnostic Assays with the ProteinChip(R) System
Andreas Wiesner 		1325
8.1 The Urgency of Earlier Diagnosis 1326
8.2 Proteins are Best Choice Again 1327
8.3 Current Tools for Protein Biomarker Detection 1328
8.4 The ProteinChip(R) System at a Glance 1329
8.5 Distinctions of the SELDI Process 1333
8.6 The Pattern TrackTM Process: From Biomarker Discovery to Assay Development 1334
8.7 Protein Variants as Disease Markers 1337
8.8 Conclusion and Outlook 1338
9 Early Detection of Lung Cancer: Metabolic Profiling of Human Breath with Ion Mobility Spectrometers
Jörg Ingo Baumbach, Wolfgang Vautz, Vera Ruzsanyi, and Lutz Freitag 		1343
9.1 Introduction 1343
9.2 Material and Methods: IMS 1345
9.3 Results and Discussion 1347
9.4 Clinical Study 1349
9.5 Conclusions 1354
Volume 4  
Part VI Advanced Application Routes for Biopharmaceuticals  
Getting Inside -- Quest for the Best and How to Improve Delivery 1361
1 Advanced Drug Delivery Systems for Biopharmaceuticals
Gesine E. Hildebrand and Stephan Harnisch 		1361
1.1 Introduction 1362
1.2 Challenges for the Administration of Biopharmaceuticals 1363
1.3 Drug Delivery Strategies 1366
1.4 Outlook 1384
Pathfinder -- New Ways for Peptides, Proteins and Co 1393
2 Poly(ethylene) Glycol Conjugates of Biopharmaceuticals in Drug Delivery
Michael D. Bentley, Mary J. Bossard, Kevin W. Burton, and Tacey X. Viegas 		1393
2.1 Introduction 1394
2.2 The Polymer 1394
2.3 Safety and Disposition of PEG 1396
2.4 PEG Reagents and Conjugation 1397
2.5 Biopharmaceutical Conjugates 1400
2.6 PEGylation of Peptides 1407
2.7 Formulations of PEGylated Biopharmaceuticals 1408
2.8 Analysis of PEG-conjugates 1411
2.9 Summary and Future Outlook 1415
3 Novel Vaccine Adjuvants Based on Cationic Peptide Delivery Systems
Karen Lingnau, Christoph Klade, Michael Buschle, and Alexander von Gabain 		1419
3.1 Vaccines and their Importance in the Fight against Human Diseases 1420
3.2 Adjuvants: An Overview 1423
3.3 Cationic Peptides as Novel Vaccine Adjuvants 1426
3.4 Cationic Antimicrobial Peptides (CAMP) as Novel Adjuvants 1433
3.5 Cationic Peptide Delivery Systems in Combination with Other Adjuvants 1437
3.6 The Development of IC31 and Future Prospects 1440
3.7 Conclusions 1440
4 The Evolving Role of OralinTM (Oral Spray Insulin) in the Treatment of Diabetes using a Novel RapidMistTM Diabetes Management System
Pankaj Modi 		1445
4.1 Introduction 1446
4.2 Rationale for OralinTM Development 1446
4.3 The Benefits of OralinTM 1447
4.4 The Preparation and Pharmaceutical Properties of OralinTM 1448
4.5 Phase II, Long-term Safety and Efficacy Study 1457
4.6 Conclusions 1460
5 Improvement of Intestinal Absorption of Peptide and Protein Biopharmaceuticals by Various Approaches
Akira Yamamoto 		1463
5.1 Improvement of Peptide and Protein Absorption 1464
5.2 Use of Protease Inhibitors 1467
5.3 Chemical Modification of Peptide and Protein Biopharmaceuticals 1472
5.4 Chitosan Capsules for the Colon-specific Delivery of Insulin 1480
5.3 Conclusion 1484
Via Mala -- the Stoney Road of DNA Delivery: Back-pack, Feed-back, and Pay-back 1487
6 DNA Vaccine Delivery from Poly(ortho ester) Microspheres
Chun Wang, Herman N. Eisen, Robert Langer, and Jorge Heller 		1487
6.1 Introduction 1488
6.2 Poly(Ortho Esters) 1494
6.3 Preparation and Characterization of Microspheres 1496
6.4 In vivo Evaluation of Immune Responses 1500
6.5 Concluding Remarks 1503
7 Liposomal In vivo Gene Delivery
Shigeru Kawakami, Fumiyoshi Yamashita, and Mitsuru Hashida 		1507
7.1 Cationic Charge-mediated In vivo Gene Transfer to the Lung 1510
7.2 Asialoglycoprotein Receptor-mediated In vivo Gene Transfer to Hepatocytes 1512
7.3 Mannose Receptor-mediated In vivo Gene Transfer to Macrophages 1513
7.4 Folate Receptor-mediated In vivo Gene Transfer to Cancer Cells 1515
7.5 Transferrin Receptor-mediated In vivo Gene Transfer to Brain 1517
7.6 Conclusions 1517
8 Programmed Packaging: A New Drug Delivery System and its Application to Gene Therapy
Kentaro Kogure, Hidetaka Akita, Hiroyuki Kamiya, and Hideyoshi Harashima 		1521
8.1 New Concept for Gene Delivery 1521
8.2 Controlled Intracellular Trafficking 1525
8.3 Transgene Expression and Gene Correction 1531
8.4 Towards Clinical Applications of Transgene Expression and Gene Correction 1534
Getting Beyond -- Rocket Science vs. Science Fiction 1537
9 Bionanotechnology and its Role to Improve Biopharmaceuticals
Oliver Kayser 		1537
9.1 Introduction 1537
9.2 Drug and Gene Delivery 1539
9.3 Gene Delivery 1543
9.4 Biosensors 1544
9.5 Implants and Tissue Engineering 1546
9.8 Safety Aspects 1548
9.7 Conclusions and Future Trends 1550
Part VII From Transcription to Prescription of Biopharmaceuticals  
Dosis Facit Venenum -- The Therapeutic Window between Systemic Toxicity and Lack of Efficacy 1557
1 Analytics in Quality Control and In vivo
Michael Hildebrand 		1557
1.1 Introduction 1558
1.2 Quality Control 1559
1.3 Classes of Biopharmaceuticals 1560
1.4 Analytical Methods and Specifications 1560
1.5 International Guidelines on Quality Control 1571
1.6 Analytics In vivo 1573
1.7 Conclusions 1577
2 Design, Development and Optimization: Crystal Structures of Microsomal Cytochromes P450
Dijana Matak Vinkovic\', Sheena Whyte, Harren Jhoti, Jose Cosme, and Pamela A. Williams 		1581
2.1 P450: The Background 1581
2.2 Importance of P450s for Drug Development 1582
2.3 Variability and Drug Metabolism 1583
2.4 The Structure of Cytochrome P450 1584
2.5 Conclusions 1599
3 MettoxTM: A Suite of Predictive In silico and In vitro Assays for Metabolic and Genotoxicological Profiling of Preclinical Drug Candidates
Michael Murray 		1603
3.1 Issues and Economics of Early ADMET (Absorption, Distribution, Metabolism, Excretion„ and Toxicity) Assessment 1604
3.2 Phase I Metabolism Prediction: Computational„ Approaches 1608
3.3 Phase I Metabolism Prediction: In vitro Techniques 1613
3.4 Genotoxicity Prediction 1624
3.5 Conclusions 1634
Happy End: Claim to Fame and Approval 1637
4 Considerations for Developing Biopharmaceuticals: FDA Perspective
Kurt Brorson, Patrick G. Swann, Janice Brown, Barbara Wilcox, and Marjorie A. Shapiro 		1637
4.1 Introduction 1638
4.2 Regulatory Authority 1639
4.3 Overview of Product Development: CMC Perspective 1643
4.4 Chemistry, Manufacturing and Controls Considerations 1645
4.5 Quality Control and Assurance 1647
4.6 Microbial Issues Specific to Biopharmaceuticals 1650
4.7 Process Validation 1653
4.8 Inspectional Considerations 1653
4.9 Biotech Development: Lessons Learned and Issues Overcome by Industry and FDA 1654
4.10 FDA Initiatives to Improve the Pharmaceutical and Biopharmaceutical Development Process 1661
5 The Regulatory Environment for Biopharmaceuticals in the EU
Axel F. Wenzel and Carina E.A. Sonnega 		1669
5.1 Introduction 1673
5.2 History and Background 1673
5.3 The Competent Regulatory Bodies 1676
5.4 What is the EU Authorities' Definition of a Biotechnological Product? 1681
5.5 The Regulatory Framework 1682
5.6 CP: The ´´Biotech´´ Procedure 1683
5.7 From Transcription to Prescription: What is Different for Biotechnological Drugs? 1688
5.8 Biogenerics 1700
5.9 Conclusions and Outlook 1701
Part VIII From Bench to Bedside -- The Aftermaths  
Think Big and Dealmaking for Growth -- Global Changes in the Health-care Sector 1711
1 Healthcare Trends and their Impact on the Biopharmaceutical Industry: Biopharmaceuticals Come of Age
Alexander Moscho, Markus A. Schäfer, and Kristin Yarema 		1711
1.1 Introduction 1712
1.2 Despite Robust Demand the Industry Faces Severe Challenges 1713
1.3 Why Biopharmaceuticals can Succeed in Rougher Markets 1724
1.4 Biopharmaceutical Players Will Need to Adapt their Portfolios and Business Models 1728
1.5 Conclusions and Outlook 1738
News and Views -- Quo Vadis, Biopharmaceuticals? 1741
2 mondoBIOTECH: The Swiss biotech BOUTIQUE
Dorian Bevec and Fabio Cavalli 		1741
2.1 Introduction  
2.2 Product Platforms 1742
2.3 Interferon- + Genechip 1750
2.4 Bacteriophages 1751
2.5 Outlook for the Company 1752
3 G-CSF and Bioequivalence: The Emergence of Healthcare Economics
James Harris, III 		1755
3.1 Introduction 1756
3.2 Biogenerics and Bioequivalence 1756
3.3 Summary and Outlook 1767
Light at the End of the Tunnel or Back to the Roots? 1771
4 Bioinformatics: From Peptides to Profiled Leads
Paul Wrede and Matthias Filter 		1771
4.1 Introduction 1772
4.2 Basic Concepts of Virtual Drug Discovery 1773
4.3 Pep2Lead Concept 1778
4.4 ADMETox Profiling 1785
4.5 Outlook 1798
5 Engineering and Overproduction of Polyketide Natural Products
Martha Lovato Tse and Chaitan Khosla 		1803
5.1 Introduction 1804
5.2 Polyketide Synthases 1806
5.3 Engineering PKSs to Produce Novel Polyketides 1815
5.4 Development of Scalable Production Processes 1820
5.5 Conclusions 1825
Epilog 1833
More about the Editor 1835
Supplement CD-ROM 1837
Subject Index 1841

 
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