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 xxvPreface xli1 The History of Therapeutic Monoclonal Antibodies 1Regis Sodoyer1.1 Summary 11.2 Introduction 11.3 New Markets for Old Antibodies, Old Markets for New Antibodies 21.4 Antibody Engineering: A New Approach to the Treatment of Disease 51.5 Fully Human Antibodies, What Else? 81.6 Antibody Design 171.7 Antibody Production 301.8 Recombinant Antibodies: No Limits… 37Acknowledgments 37References 372 Structure, Classification, and Naming of Therapeutic Monoclonal Antibodies 63Zhinan Xia2.1 Summary 632.2 Introduction 642.3 Antibody Structure 652.4 Classification of Antibodies 712.5 IgG Subtype 732.6 Nomenclature of Therapeutic mAbs 732.7 List of Therapeutic mAbs on Market or in Review in the European Union and the United States 82References 823 Mechanism of Action for Therapeutic Antibodies 85Yu Zhou and James D. Marks3.1 Introduction 853.2 Blockade of Ligand–Receptor Interaction 863.3 Target Depletion via ADCC and CDC 943.4 Engaging Cytotoxic T Cell Through the Use of Bispecific Abs 953.5 Receptor Downregulation by Enhanced Internalization and Degradation 963.6 Targeted Drug Delivery 963.7 Summary 98References 984 Therapeutic Monoclonal Antibodies and Their Targets 113Jose 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-Internati4.1 Summary 1134.2 Introduction 1144.3 Monoclonal Antibody Therapies for Infectious Diseases 1174.4 Monoclonal Antibody Therapies for Autoimmune Diseases 1204.5 Therapeutic Monoclonal Antibodies Against Neoplastic Diseases 1274.6 Conclusion 138References 1405 Antibody Posttranslational Modifications 155Roy Jefferis5.1 Summary 1555.2 Introduction 1555.3 Overview of Co- and Posttranslational Modifications 1575.4 Glycosylation 1625.5 Glycation 1725.6 IgG-Fab Glycosylation 1795.7 The Influence of Expression Platform on CTM/PTMs and Unintended Physicochemical Changes 1815.8 Human Antibody Isotypes Other than IgG 1825.9 Conclusion 182References 1836 The Pharmacology, Pharmacokinetics, and Pharmacodynamics of Antibodies 201Ningning Xu, Meimei Liu, and Margaret Liu6.1 Summary 2016.2 Introduction 2016.3 Pharmacology of Anticancer MAbs 2026.4 Antibody Pharmacokinetics 2046.5 Pharmacodynamics 2086.6 Conclusions 211References 2117 Monoclonal Antibodies: Applications in Clinical Oncology 217Jeanene (“Gigi”) Robison7.1 Summary 2177.2 Introduction 2177.3 Ado-trastuzumab Emtansine (Anti-HER2 Antibody Conjugated with Emtansine, Kadcyla®) 2187.4 Alemtuzumab (Campath®, Campath-1H) 2207.5 Bevacizumab (Avastin) 2217.6 Brentuximab Vedotin (Anti-CD30 Antibody, Adcetris®) 2257.7 Cetuximab (Anti-EGFR Antibody, Erbitux®) 2277.8 Denosumab (Anti-RANKL Antibody, Xgeva™; Prolia™) 2307.9 Eculizumab (Anti-C5 Antibody, Soliris®) 2337.10 Ibritumomab Tiuxetan (Anti-CD20 Antibody, Zevalin®) 2357.11 Ipilimumab (Anti-CTLA-4 Antibody, Yervoy®) 2377.12 Obinutuzumab (Gazyva®) 2387.13 Ofatumumab (Anti-CD20 Antibody, Arzerra®) 2407.14 Panitumumab (Anti-EGFR Antibody, Vectibix™) 2427.15 Pembrolizumab (Keytruda®) 2447.16 Pertuzumab (Perjeta®) 2467.17 Ramucirumab (Cyramza®) 2487.18 Rituximab (Anti-CD20 Antibody, Rituxan) 2507.19 Tositumomab and Iodine I-131 Tositumomab (Anti-CD20 Antibody, Bexxar®) 2567.20 Trastuzumab (Anti-HER2 Antibody, Herceptin®) 258References 2628 Development of Biosimilar Rituximab and Clinical Experience 269Reena Nair8.1 Summary 2698.2 Introduction 2708.3 Reditux Development Overview 2718.4 Preclinical and Toxicology Studies 2768.5 Clinical Evaluation 2768.6 Conclusions 280References 2809 Monoclonal Antibodies for Infectious Diseases 283Steven J. Projan9.1 Summary 2839.2 Into the Future: Prophylaxis and Precision Medicine 2839.3 Immune Therapy: A Noble Undertaking that Went to the Dogs 2849.4 What’s Taking So Long? 2859.5 Staphylococcus aureus: Still Public Enemy Number One? 2859.6 Pseudomonas aeruginosa: The Bacterial Cockroach 2869.7 Immune Evasion and Degree of Difficulty 2879.8 Clostridium difficile: You Can’t Win for Losing 2879.9 If Two Is Enough, Is Six Too Many? mAb Combos 2889.10 Prophylaxis or Therapy? When You Come to a Fork in the Road, Take It 2889.11 Influenza and Plan “B” 2889.12 Safety: Human Enough for You? 2889.13 Another Precinct Is Heard from Immunomodulatory Agents for the Treatment of Chronic Infections 2899.14 Are We There Yet? Easy to Use, Fast Turnaround, Point-of-Care Diagnostics 2899.15 Yeah but Aren’t These (Biologic) Drugs Going to Be Expensive? 290References 29010 Monoclonal Antibodies for Musculoskeletal, CNS, and Other Diseases 293Junming Yie and Tao Wu10.1 Summary 29310.2 Natalizumab (Tysabri®) 29410.3 Eculizumab (Soliris®) 29710.4 Ranibizumab (Lucentis®) 30010.5 Denosumab (Prolia® and Xgeva®) 30410.6 Antibody Therapies for Solid Organ Transplantation (Muromonab-CD3 (Orthoclone OKT3®), Basiliximab (Simulect®), and Daclizumab (Zenapax®)) 30710.7 Conclusion 314References 31811 Manufacture of Recombinant Therapeutic Proteins Using Chinese Hamster Ovary Cells in Large-Scale Bioreactors: History, Methods, and Perspectives 327Florian M. Wurm and Maria de Jesus11.1 Summary 32711.2 Introduction 32911.3 Process and Cells: The Quasi-species Concept Explains Individualized Development Needs 33211.4 Choices for Manufacturing: Host Cells for Production and Suitable Selection Systems 33511.5 Methods for Rapid Generation of High-Producing Cell Lines 33711.6 Silencing: Stability of Expression, Facilitators for High-Level Productivity 33911.7 High-Throughput Bioprocess Development 34011.8 Disposable Bioreactors 34211.9 Nonclonal Expression Technologies for Fast Production and Assessment of Expression Potential and Quality 34311.10 Conclusions 345Conflict of Interest 346References 34612 Process Development 355Samuel D. Stimple and David W. Wood12.1 Summary 35512.2 Introduction 35512.3 Protein A and Protein G Batch Affinity Chromatography 35612.4 Alternatives to Protein A 35812.5 Disposables and Continuous Downstream Processing 36112.6 Conclusion 373References 37413 Biosimilars and Biobetters: Impact on Biopharmaceutical Manufacturing and CMOs 381Ronald A. Rader13.1 Summary 38113.2 Introduction 38213.3 The Biosimilar Pipeline 38313.4 Developing Countries Will Continue to Prefer Cheaper Biogenerics 38613.5 Biosimilar Candidates in the Pipeline 38713.6 Biosimilar Development by Country/Region 38713.7 Biosimilars Impact on Biopharmaceutical Markets and the Industry 38913.8 Marketing Biosimilars Will Be a Challenge 39113.9 Biosimilar Manufacturing Will Be State of the Art 39113.10 Biosimilars Will Increase Demand for Product Quality and Transparency 39213.11 CMOs Benefit from Biosimilars 39313.12 Conclusions 394References 39514 Cell Line and Cell Culture Development for Biosimilar Antibody-Drug Manufacturing 397Jianguo Yang14.1 Summary 39714.2 Mammalian Cell Line Development 39814.3 Cell Culture Process Development 40614.4 Future Trends 418References 41915 Product Analysis of Biosimilar Antibodies 427Weidong Jiang, Scott Liu, and Ziyang Zhong15.1 Summary 42715.2 Introduction 42815.3 Identity 42815.4 Purity and Impurities 43815.5 Stability 44515.6 Quantity—Concentration Measurement 44615.7 Biological Activity—Functional Bioassays 44615.8 Efficacy and Safety: Animal Studies for Antibody-Drug Efficacy, PK/PD, and Toxicity 450References 45216 Bioanalytical Development 459Rafiq Islam16.1 Summary 45916.2 Introduction 45916.3 Pharmacodynamics Characterization 46016.4 Pharmacokinetic Assessment 46516.5 Immunogenicity Assessment 47216.6 Conclusion 474References 47517 Preclinical and Clinical Development of Biosimilar Antibodies 479João Eurico Fonseca and João Gonçalves17.1 Summary 47917.2 Introduction 48017.3 Quality and Preclinical Development of Biosimilar Monoclonal Antibodies 48117.4 Extrapolation of Indications 49017.5 Clinical Development of Biosimilars of Monoclonal Antibodies 49217.6 Ongoing Trials of Candidate Biosimilars of Monoclonal Antibodies 49417.7 Conclusion 498References 49818 Regulatory Issues 505Clarinda Islam18.1 Summary 50518.2 Introduction 50518.3 Existing Regulatory Pathways 50618.4 Challenges 51218.5 Conclusion 514References 51419 Legal Considerations 517K. Lance Anderson, Jennifer R. Moore Meline, and Jonathan D. Ball19.1 Summary 51719.2 Overview of the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) 51919.3 Patent Litigation and the BPCIA 52919.4 Patenting Your Biosimilar 54119.5 Conclusion 543Notes 54420 ADCC Enhancement Technologies for Next-Generation Therapeutic Antibodies 549Cheng Liu and Su Yan20.1 Summary 54920.2 Introduction 54920.3 Activation of ADCC Functions 55020.4 ADCC Enhancement through Glycol-Engineering Technologies 55220.5 Major ADCC Enhancement through Glycol-Engineering Technologies 55320.6 ADCC Enhancement through Fc Mutagenesis 55720.7 Major ADCC Enhancement Fc Mutagenesis Technologies 55720.8 Conclusion 559References56021 Antibody Half-Life: Engineering for Optimal Performance 565K. John Morrow, Jr.21.1 Summary 56521.2 Introduction 56621.3 The IgG Molecule as a Therapeutic Entity 56821.4 FcRn and Antibody Half-Life 56921.5 Optimizing Antibody Fragments’ Half-Life 57221.6 Albumin Fusions for Half-Life Extension 57521.7 Mice as Models for Human Disease 57721.8 Half-Life Engineering: Present and Future 57821.9 A Bright Future for Biosimilars, Biobetters, and Improved Half-Life Modifications 583References 58522 Technologies for Antibody-Drug Conjugation 591Patrick G. Holder and David Rabuka22.1 Summary 59122.3 The Importance of Therapeutic Index 59222.4 ADC Construction: Building from the Protein Out 59322.5 Conjugation Sites and Heterogeneity 59622.6 Installation of Conjugation Sites 59722.7 Bioconjugation Reactions 60222.8 Linking Antibodies and Payloads 61322.9 Conclusion 623References 623Index 641