Biosimilars of Monoclonal Antibodies

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.

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