Biosimilars of Monoclonal Antibodies A Practical Guide to Manufacturing, Preclinical, and Clinical Development
, by Liu, Cheng; Morrow, K. John
- ISBN: 9781118662311 | 1118662318
- Cover: Hardcover
- Copyright: 12/19/2016
Addressing a significant need by describing the science and process involved to develop biosimilars of monoclonal antibody (mAb) drugs, this book covers all aspects of biosimilar development: preclinical, clinical, regulatory, manufacturing.
• Guides readers through the complex landscape involved with developing biosimilar versions of monoclonal antibody (mAb) drugs
• Features flow charts, tables, and figures that clearly illustrate processes and makes the book comprehensible and accessible
• Includes a review of FDA-approved mAb drugs as a quick reference to facts and useful information
• Examines new technologies and strategies for improving biosimilar mAbs
Cheng Liu, PhD, is founder and CEO of Eureka Therapeutics, a biotech company dedicated to monoclonal antibody drug discovery and development for unmet medical needs. He is an expert on therapeutic antibody and engineering, and a frequent speaker at pharmaceutical conferences. He holds multiple issued US and international patents in the field of therapeutic antibody discovery and engineering and has authored many scientific publications in the field of cancer immunotherapy. Dr. Liu was awarded Special Congressional Recognition for his contributions to improving human health in 2007.
K. John Morrow, Jr., PhD, is President and CEO of Newport Biotechnology Consultants, and has worked in academia and in the private sector. He has published a total of over 280 peer-reviewed articles, reports in biotechnology trade papers, chapters in books, and full length books. He serves as a consultant for Meridian Bioscience, Inc., in Cincinnati, OH and for Point A Consulting in Louisville, KY.
K. John Morrow, Jr., PhD, is President and CEO of Newport Biotechnology Consultants, and has worked in academia and in the private sector. He has published a total of over 280 peer-reviewed articles, reports in biotechnology trade papers, chapters in books, and full length books. He serves as a consultant for Meridian Bioscience, Inc., in Cincinnati, OH and for Point A Consulting in Louisville, KY.
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™; Prolia™) 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™) 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 Existing Regulatory Pathways 506
18.4 Challenges 512
18.5 Conclusion 514
References 514
19 Legal Considerations 517
K. Lance Anderson, Jennifer R. Moore Meline, and Jonathan D. Ball
19.1 Summary 517
19.2 Overview of the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) 519
19.3 Patent Litigation and the BPCIA 529
19.4 Patenting Your Biosimilar 541
19.5 Conclusion 543
Notes 544
20 ADCC Enhancement Technologies for Next-Generation Therapeutic Antibodies 549
Cheng Liu and Su Yan
20.1 Summary 549
20.2 Introduction 549
20.3 Activation of ADCC Functions 550
20.4 ADCC Enhancement through Glycol-Engineering Technologies 552
20.5 Major ADCC Enhancement through Glycol-Engineering Technologies 553
20.6 ADCC Enhancement through Fc Mutagenesis 557
20.7 Major ADCC Enhancement Fc Mutagenesis Technologies 557
20.8 Conclusion 559
References
560
21 Antibody Half-Life: Engineering for Optimal Performance 565
K. John Morrow, Jr.
21.1 Summary 565
21.2 Introduction 566
21.3 The IgG Molecule as a Therapeutic Entity 568
21.4 FcRn and Antibody Half-Life 569
21.5 Optimizing Antibody Fragments’ Half-Life 572
21.6 Albumin Fusions for Half-Life Extension 575
21.7 Mice as Models for Human Disease 577
21.8 Half-Life Engineering: Present and Future 578
21.9 A Bright Future for Biosimilars, Biobetters, and Improved Half-Life Modifications 583
References 585
22 Technologies for Antibody-Drug Conjugation 591
Patrick G. Holder and David Rabuka
22.1 Summary 591
22.3 The Importance of Therapeutic Index 592
22.4 ADC Construction: Building from the Protein Out 593
22.5 Conjugation Sites and Heterogeneity 596
22.6 Installation of Conjugation Sites 597
22.7 Bioconjugation Reactions 602
22.8 Linking Antibodies and Payloads 613
22.9 Conclusion 623
References 623
Index 641
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