Current Trends in Monoclonal Antibody Development and Manufacturing (eBook)

Steven J. Shire, Wayne Gombotz, Karoline Bechtold-Peters, James Andya (Herausgeber)

eBook Download: PDF

2009 | 2010
XIV, 354 Seiten
Springer New York (Verlag)
978-0-387-76643-0 (ISBN)

Infos

Monoclonal antibodies represent one of the fastest growing areas of new drug development within the pharmaceutical industry. Several blockbuster products have been approved over the past several years including Rituxan, Remicade, Avastin, Humira, and Herceptin. In addition, over 300 new drugs are currently in clinical trials. With both large, established biotechnology companies and small start-ups involved in the development of this important class of molecules, monoclonal antibodies products will become increasingly prevalent over the next decade.

Recently the regulatory review of monoclonal antibodies has been moved from Center for Biologics and Research to the Center for Drug Evaluation and Research (CDER) division of the US Food and Drug Administration. It is anticipated that CDER will expect a certain minimal amount of data to be provided as more of these products move through the regulatory pipeline. Current Trends in Monoclonal Antibody Development and Manufacturing will provide readers with an understanding of what is currently being done in the industry to develop, manufacture, and release monoclonal antibody products and what will be required for a successful regulatory submission.

Inhalt

Preface 6
Contents 9
Contributors 11
1 Introduction 15
1. Overview of Monoclonal Antibodies 15
2. Advantages of MAbs as Drugs 18
3. Challenges with MAb Development 18
References 19
2 CDR Repair: A Novel Approach to Antibody Humanization 21
Abbreviations 21
1. Important Considerations 23
2. Humanization Approaches 26
3. Humanization Methods 29
4. Antibody Properties 36
5. Minimizing Immunogenic Potential 36
6. Conclusions 37
References 38
3 Nanobodies, Single-Domain Antigen- Binding Fragments of Camelid Heavy- Chain Antibodies 41
Abbreviations 41
1. Introduction 41
2. Heavy-Chain Antibodies 43
3. Isolation of Antigen-Specific Nanobodies 45
4. Interesting Features of Nanobodies 47
5. Applications of Nanobodies 50
6. Conclusion 53
References 53
4 GPEx® A Flexible Method for the Rapid Generation of Stable, High Expressing, Antibody Producing Mammalian Cell Lines 62
1. Introduction 62
2. Benefits of the GPEx® Cell Line Development Technology for Production of Antibodies 62
3. Generation of Antibody Producing Cell Lines 64
4. Antibody Screening from Pooled Cell Lines 67
5. Clonal Cell Line Development 68
6. Pooled Cell Line Re-transduction 69
7. Clonal Cell Line Stability 69
8. Upstream Process Development of Antibody Cell Lines 71
9. Conclusions 72
References 73
5 Advancing Our Cell Culture Platform: Incorporating Lessons Learned and New Technologies 74
1. Introduction 74
2. Implementing a Platform 75
3. Components of the Platform 76
4. Platform Metrics 77
5. Platform Challenges 78
6. Evolving the Platform 80
7. Vision for the Future 82
8. Conclusions 83
6 Addressing Changes Associated with Technology Transfer: A Case Study 85
1. Introduction 85
2. Defined Process Changes 85
3. Comparability of the Malvern Process 88
4. The Need for an Additional Process Improvement 89
5. Impact of Product Breakthrough and Precipitate in the Feed Stream 93
6. Defining the Process Improvement 94
7. Conclusions 95
7 Concepts for Disposables in Biopharmaceutical Manufacture 96
1. Introduction 96
2. The Rationale for Single-Use Concepts 97
3. Counting the Cost 97
4. Validation 99
5. Logistics and Environmental Impact 100
6. Limitations of the Disposable Concept 100
7. Upstream Production 101
8. Downstream Processing: Initial Recovery 102
9. Downstream Processing: Chromatography 102
10. Economic and Performance Case Study 104
11. Conclusions 106
References 106
8 Formulation and Delivery Issues for Monoclonal Antibody Therapeutics 110
1. Introduction 110
2. Antibody Characteristics Relevant for Formulation and Delivery 112
3. General Concerns for Antibody Formulations 113
4. Stability Issues for Antibody formulations 114
5. Strategies to Stabilize Antibody Formulations 119
6. Formulation Issues for Alternative Forms of Antibody Delivery 122
7. Other Delivery Issues 127
8. Conclusions: Challenges and Opportunities 129
References 131
9 Challenges in the Development of High Protein Concentration Formulations 137
1. Introduction 138
2. Solubility Considerations 138
3. Stability Considerations 141
4. Manufacturing Considerations 143
5. Cost of Goods and Delivery Considerations 146
6. Analytical Considerations 147
7. Summary and Conclusions 150
References 150
10 Protein Immobilization by Crystallization and Precipitation: An Alternative to Lyophilization 154
1. Introduction: Advantages and Limitations of Lyophilization 154
2. Alternative Immobilization and Drying Methods Appropriate for Biomolecule Processing 155
3. Extraction of Water by Crystallization and Precipitation 158
4. Immobilization on Carriers: An Outlook into Adjacent Areas 173
References 176
11 Characterizing High Affinity Antigen/ Antibody Complexes by Kinetic and Equilibrium Based Methods 182
Abbreviations 182
1. Introduction 182
2. Materials and Methods 183
3. Results 186
4. Discussion 191
References 194
12 Analytical Characterization of Monoclonal Antibodies: Linking Structure to Function 196
Abbreviations 196
1. Introduction 196
2. Fc Glycosylation 197
3. The Role of Fc Glycans on the Clearance of IgG1- Type Antibodies 199
4. Heavy Chain C-Terminal Lysine Processing 201
5. Hinge-Region Fragmentation 202
6. Glycation 202
7. Unpaired Cysteines 203
8. Aspartate Isomerization 204
9. Discussion 205
References 206
13 Analysis of Irreversible Aggregation, Reversible Self- association and Fragmentation of Monoclonal Antibodies by Analytical Ultracentrifugation 209
1. Introduction: Classes of Protein Aggregates and Protein Aggregation and Pharmaceutical Development 209
2. Methods for Analysis of Protein Size Distribution 211
3. What is Analytical Ultracentrifugation? 213
4. Analytical Ultracentrifugation Theory 214
5. Application of Analytical Ultracentrifugation 215
6. Method Optimization to Evaluate Trace Amounts of Aggregate 219
7. Summary of Experimental Configurations to Improve Reproducibility 226
References 228
14 Biophysical Signatures of Monoclonal Antibodies 230
1. Introduction 230
2. Materials and Methods 231
3. General Biophysical Properties of Monoclonal Antibodies 234
4. Solubility 243
5. Discussion 244
References 246
15 Impact of Fc Glycosylation on Monoclonal Antibody Effector Functions and Degradation by Proteases 249
1. Introduction 249
2. Biosynthesis of Fc Glycans 250
3. Heterogeneity of Fc Glycans 250
4. Human IgG Glycosylation 252
5. Species Specificity of IgG Glycans 253
6. Disease Specific Glycosylation of IgGs 254
7. Glycosylation in Recombinant IgGs 254
8. Antibody Effector Functions and IgG Glycosylation 256
9. IgG Cleaving Proteases 257
10. Fc Glycosylation Increases Antibody Resistance to Papain 259
11. Role of Terminal Sugars on Antibody Resistance to Papain 259
12. Effect of Fc Glycans on Antibody Structure 260
13. G2 Oligosaccharide Structure 261
14. The Carbohydrate Structure Comparison of G2 and G0 Complexes 261
15. Conclusions 263
References 264
16 Immunogenicity Assessment of Antibody Therapeutics 270
1. Introduction 270
2. Immunogenicity Drivers 271
3. Strategies to Identify Anti-drug Antibodies 273
4. Non-clinical Immunogenicity Testing 275
5. Conclusions 284
References 285
17 Production of Monoclonal Antibodies in E. coli 292
Abbreviations 292
1. Introduction 292
2. E. coli Challenges 293
3. Expression Construct Design 293
4. Promoters 294
5. Signal Sequences 294
6. Control of Each Chain 295
7. Chaperone Over-Expression 296
8. Optimized Construct 296
9. Host Strains 296
10. Fermentation Scale Up 297
11. Antibody Characterization 300
12. Conclusion 303
References 304
18 Recent Advancements in the Use of Antibody Drug Conjugates for Cancer Therapy 306
1. Introduction 306
2. Optimization of ADC Drug and Linker Components 306
3. Optimization of the Conjugation Technology 313
4. Conclusion 314
References 314
19 Antibody Radiolabeling 320
1. Introduction 320
2. Radiolabeling Antibodies with Radiohalogens 324
3. Radiolabeling of Antibodies with Radiometals 328
4. Manufacturing of Radiolabeled Antibodies 333
References 337
Index 342

Produkt-Details

• Erscheint lt. Verlag: 11.11.2009
• Reihe/Serie: Biotechnology: Pharmaceutical Aspects
• Reihe/Serie: Biotechnology: Pharmaceutical Aspects
• Zusatzinfo: XIV, 354 p.
• Verlagsort: New York
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Gesundheitsfachberufe
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Humanbiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Zoologie
• Schlagworte: antibodies • Antigen • Aspects • Monoclonal • Pharmaceutical • Shire
• ISBN-10: 0-387-76643-X / 038776643X
• ISBN-13: 978-0-387-76643-0 / 9780387766430