Hjem

Notes on Contributors xxv Preface xli 1 The History of Therapeutic Monoclonal Antibodies 1 Regis Sodoyer
1.1 Summary 1
1.2 Introduction 1
1.3 New Markets for Old Antibodies, Old Markets for New Antibodies 2
1.4 Antibody Engineering: A New Approach to the Treatment of Disease 5
1.5 Fully Human Antibodies, What Else? 8
1.6 Antibody Design 17
1.7 Antibody Production 30
1.8 Recombinant Antibodies: No Limits... 37 Acknowledgments 37 References 37 2 Structure, Classification, and Naming of Therapeutic Monoclonal Antibodies 63 Zhinan Xia
2.1 Summary 63
2.2 Introduction 64
2.3 Antibody Structure 65
2.4 Classification of Antibodies 71
2.5 IgG Subtype 73
2.6 Nomenclature of Therapeutic mAbs 73
2.7 List of Therapeutic mAbs on Market or in Review in the European Union and the United States 82 References 82 3 Mechanism of Action for Therapeutic Antibodies 85 Yu Zhou and James D. Marks
3.1 Introduction 85
3.2 Blockade of Ligand-Receptor Interaction 86
3.3 Target Depletion via ADCC and CDC 94
3.4 Engaging Cytotoxic T Cell Through the Use of Bispecific Abs 95
3.5 Receptor Downregulation by Enhanced Internalization and Degradation 96
3.6 Targeted Drug Delivery 96
3.7 Summary 98 References 98 4 Therapeutic Monoclonal Antibodies and Their Targets 113 Jose A. Figueroa, Camilo Pena, Leonardo Mirandola, Adair Reidy, J. Drew Payne, Nattamol Hosiriluck, Natallia Suvorava, Rakhshanda Layeequr Rahman, Adrienne R. Whitlow, Rashmi Verma, Everardo Cobos, and Maurizio Chiriva-Internati
4.1 Summary 113
4.2 Introduction 114
4.3 Monoclonal Antibody Therapies for Infectious Diseases 117
4.4 Monoclonal Antibody Therapies for Autoimmune Diseases 120
4.5 Therapeutic Monoclonal Antibodies Against Neoplastic Diseases 127
4.6 Conclusion 138 References 140 5 Antibody Posttranslational Modifications 155 Roy Jefferis
5.1 Summary 155
5.2 Introduction 155
5.3 Overview of Co- and Posttranslational Modifications 157
5.4 Glycosylation 162
5.5 Glycation 172
5.6 IgG-Fab Glycosylation 179
5.7 The Influence of Expression Platform on CTM/PTMs and Unintended Physicochemical Changes 181
5.8 Human Antibody Isotypes Other than IgG 182
5.9 Conclusion 182 References 183 6 The Pharmacology, Pharmacokinetics, and Pharmacodynamics of Antibodies 201 Ningning Xu, Meimei Liu, and Margaret Liu
6.1 Summary 201
6.2 Introduction 201
6.3 Pharmacology of Anticancer MAbs 202
6.4 Antibody Pharmacokinetics 204
6.5 Pharmacodynamics 208
6.6 Conclusions 211 References 211 7 Monoclonal Antibodies: Applications in Clinical Oncology 217 Jeanene ("Gigi") Robison
7.1 Summary 217
7.2 Introduction 217
7.3 Ado-trastuzumab Emtansine (Anti-HER2 Antibody Conjugated with Emtansine, Kadcyla®) 218
7.4 Alemtuzumab (Campath®, Campath-1H) 220
7.5 Bevacizumab (Avastin) 221
7.6 Brentuximab Vedotin (Anti-CD30 Antibody, Adcetris®) 225
7.7 Cetuximab (Anti-EGFR Antibody, Erbitux®) 227
7.8 Denosumab (Anti-RANKL Antibody, Xgeva(tm); Prolia(tm)) 230
7.9 Eculizumab (Anti-C5 Antibody, Soliris®) 233
7.10 Ibritumomab Tiuxetan (Anti-CD20 Antibody, Zevalin®) 235
7.11 Ipilimumab (Anti-CTLA-4 Antibody, Yervoy®) 237
7.12 Obinutuzumab (Gazyva®) 238
7.13 Ofatumumab (Anti-CD20 Antibody, Arzerra®) 240
7.14 Panitumumab (Anti-EGFR Antibody, Vectibix(tm)) 242
7.15 Pembrolizumab (Keytruda®) 244
7.16 Pertuzumab (Perjeta®) 246
7.17 Ramucirumab (Cyramza®) 248
7.18 Rituximab (Anti-CD20 Antibody, Rituxan) 250
7.19 Tositumomab and Iodine I-131 Tositumomab (Anti-CD20 Antibody, Bexxar®) 256
7.20 Trastuzumab (Anti-HER2 Antibody, Herceptin®) 258 References 262 8 Development of Biosimilar Rituximab and Clinical Experience 269 Reena Nair
8.1 Summary 269
8.2 Introduction 270
8.3 Reditux Development Overview 271
8.4 Preclinical and Toxicology Studies 276
8.5 Clinical Evaluation 276
8.6 Conclusions 280 References 280 9 Monoclonal Antibodies for Infectious Diseases 283 Steven J. Projan
9.1 Summary 283
9.2 Into the Future: Prophylaxis and Precision Medicine 283
9.3 Immune Therapy: A Noble Undertaking that Went to the Dogs 284
9.4 What''s Taking So Long? 285
9.5 Staphylococcus aureus: Still Public Enemy Number One? 285
9.6 Pseudomonas aeruginosa: The Bacterial Cockroach 286
9.7 Immune Evasion and Degree of Difficulty 287
9.8 Clostridium difficile: You Can''t Win for Losing 287
9.9 If Two Is Enough, Is Six Too Many? mAb Combos 288
9.10 Prophylaxis or Therapy? When You Come to a Fork in the Road, Take It 288
9.11 Influenza and Plan "B" 288
9.12 Safety: Human Enough for You? 288
9.13 Another Precinct Is Heard from Immunomodulatory Agents for the Treatment of Chronic Infections 289
9.14 Are We There Yet? Easy to Use, Fast Turnaround, Point-of-Care Diagnostics 289
9.15 Yeah but Aren''t These (Biologic) Drugs Going to Be Expensive? 290 References 290 10 Monoclonal Antibodies for Musculoskeletal, CNS, and Other Diseases 293 Junming Yie and Tao Wu
10.1 Summary 293
10.2 Natalizumab (Tysabri®) 294
10.3 Eculizumab (Soliris®) 297
10.4 Ranibizumab (Lucentis®) 300
10.5 Denosumab (Prolia® and Xgeva®) 304
10.6 Antibody Therapies for Solid Organ Transplantation (Muromonab-CD3 (Orthoclone OKT3®), Basiliximab (Simulect®), and Daclizumab (Zenapax®)) 307
10.7 Conclusion 314 References 318 11 Manufacture of Recombinant Therapeutic Proteins Using Chinese Hamster Ovary Cells in Large-Scale Bioreactors: History, Methods, and Perspectives 327 Florian M. Wurm and Maria de Jesus
11.1 Summary 327
11.2 Introduction 329
11.3 Process and Cells: The Quasi-species Concept Explains Individualized Development Needs 332
11.4 Choices for Manufacturing: Host Cells for Production and Suitable Selection Systems 335
11.5 Methods for Rapid Generation of High-Producing Cell Lines 337
11.6 Silencing: Stability of Expression, Facilitators for High-Level Productivity 339
11.7 High-Throughput Bioprocess Development 340
11.8 Disposable Bioreactors 342
11.9 Nonclonal Expression Technologies for Fast Production and Assessment of Expression Potential and Quality 343
11.10 Conclusions 345 Conflict of Interest 346 References 346 12 Process Development 355 Samuel D. Stimple and David W. Wood
12.1 Summary 355
12.2 Introduction 355
12.3 Protein A and Protein G Batch Affinity Chromatography 356
12.4 Alternatives to Protein A 358
12.5 Disposables and Continuous Downstream Processing 361
12.6 Conclusion 373 References 374 13 Biosimilars and Biobetters: Impact on Biopharmaceutical Manufacturing and CMOs 381 Ronald A. Rader
13.1 Summary 381
13.2 Introduction 382
13.3 The Biosimilar Pipeline 383
13.4 Developing Countries Will Continue to Prefer Cheaper Biogenerics 386
13.5 Biosimilar Candidates in the Pipeline 387
13.6 Biosimilar Development by Country/Region 387
13.7 Biosimilars Impact on Biopharmaceutical Markets and the Industry 389
13.8 Marketing Biosimilars Will Be a Challenge 391
13.9 Biosimilar Manufacturing Will Be State of the Art 391
13.10 Biosimilars Will Increase Demand for Product Quality and Transparency 392
13.11 CMOs Benefit from Biosimilars 393
13.12 Conclusions 394 References 395 14 Cell Line and Cell Culture Development for Biosimilar Antibody-Drug Manufacturing 397 Jianguo Yang
14.1 Summary 397
14.2 Mammalian Cell Line Development 398
14.3 Cell Culture Process Development 406
14.4 Future Trends 418 References 419 15 Product Analysis of Biosimilar Antibodies 427 Weidong Jiang, Scott Liu, and Ziyang Zhong
15.1 Summary 427
15.2 Introduction 428
15.3 Identity 428
15.4 Purity and Impurities 438
15.5 Stability 445
15.6 Quantity--Concentration Measurement 446
15.7 Biological Activity--Functional Bioassays 446
15.8 Efficacy and Safety: Animal Studies for Antibody-Drug Efficacy, PK/PD, and Toxicity 450 References 452 16 Bioanalytical Development 459 Rafiq Islam
16.1 Summary 459
16.2 Introduction 459
16.3 Pharmacodynamics Characterization 460
16.4 Pharmacokinetic Assessment 465
16.5 Immunogenicity Assessment 472
16.6 Conclusion 474 References 475 17 Preclinical and Clinical Development of Biosimilar Antibodies 479 João Eurico Fonseca and João Gonçalves
17.1 Summary 479
17.2 Introduction 480
17.3 Quality and Preclinical Development of Biosimilar Monoclonal Antibodies 481
17.4 Extrapolation of Indications 490
17.5 Clinical Development of Biosimilars of Monoclonal Antibodies 492
17.6 Ongoing Trials of Candidate Biosimilars of Monoclonal Antibodies 494
17.7 Conclusion 498 References 498 18 Regulatory Issues 505 Clarinda Islam
18.1 Summary 505
18.2 Introduction 505
18.3 Exis