Table of Contents

Cover

Related Titles

Title Page

Quick Reference List of Antibodies by International Nonproprietary Name

Quick Reference List of Antibodies by Brand Name

A Greeting by the Editors

Foreword to the First Edition

Foreword to the Second Edition

List of Contributors

Abbreviations

Appendix: Marketed Monoclonal Antibodies Compendium

Volume I: Def ining the Right Antibody Composition

Chapter 1: Therapeutic Antibodies – from Past to Future
1. 1.1 An Exciting Start – and a Long Trek
2. 1.2 The Gold Rush
3. 1.3 Success and Setbacks
4. 1.4 The Gleaming Horizon
5. References
6. Further Reading

Part I: Selecting and Shaping the Antibody Molecule

Chapter 2: Selection Strategies for Monoclonal Antibodies
1. 2.1 Introduction
2. 2.2 Historical Remarks
3. 2.3 Antibody Structure and Function
4. 2.4 Production of Monoclonal Antibodies
5. 2.5 Purification and Modification of Monoclonal Antibodies
6. 2.6 Monoclonal Antibodies for Tumor Therapy
7. 2.7 Outlook
8. References
Chapter 3: Antibody Phage Display
1. 3.1 Introduction
2. 3.2 Phage Display
3. 3.3 Selection and Screening
4. 3.4 Phage Display Vectors
5. 3.5 Phage Display Libraries
6. 3.6 Construction of Phage Display Libraries
7. Acknowledgments
8. References
Chapter 4: Transgenic Animals Derived by DNA Microinjection
1. 4.1 Introduction
2. 4.2 Construction of Human Ig Transloci
3. 4.3 BAC Integration
4. 4.4 Designer Zinc Finger Endonucleases to Silence Endogenous Ig Loci
5. 4.5 Expression Comparison of Fully Human and Chimeric IgH Loci
6. 4.6 Outlook
7. References
Chapter 5: Humanization Strategies
1. 5.1 Introduction
2. 5.2 History of Humanization
3. 5.3 CDR-Grafting
4. 5.4 The Design Cycle
5. 5.5 Other Approaches to Antibody Humanization
6. References
Chapter 6: Antibody Affinity
1. 6.1 Introduction
2. 6.2 Affinity Maturation
3. 6.3 Antibody Affinity: Antigen Binding and Potency
4. 6.4 Binding and Potency In Vitro
5. 6.5 Binding and Potency In Vivo
6. 6.6 Selection of High-Affinity Antibodies from Hybridoma Cell Lines
7. 6.7 Generation of Antibodies against Soluble Antigens
8. 6.8 Generation of Antibodies against Cell Surface Antigens
9. 6.9 Determination of Antibody Affinity
10. 6.10 Surface Plasmon Resonance
11. 6.11 Other Methods for Determining Antibody Affinity
12. 6.12 Conclusion
13. References
Chapter 7: Fc Engineering
1. 7.1 Mechanisms of Action of Monoclonal Antibodies
2. 7.2 Modifying Effector Functions
3. 7.3 Modifying Antibodies' Pharmacokinetics
4. 7.4 Summary and Conclusions
5. References
Chapter 8: Glycosylation of Antibody Molecules
1. 8.1 Introduction
2. 8.2 Overview of the IgG Molecule
3. 8.3 Quaternary Structure of IgG-Fc: The Protein Moiety
4. 8.4 The IgG-Fc Oligosaccharide Moiety
5. 8.5 IgG-Fc Protein/Oligosaccharide Interactions
6. 8.6 Protective Mechanisms Activated by Immune Complexes
7. 8.7 Role of IgG Glycoforms in Recognition by Cellular FγRs
8. 8.8 The Influence of Fucose and Bisecting N-Acetylglucosamine on IgG-Fc Activities
9. 8.9 The Influence of Galactosylation on IgG-Fc Activities
10. 8.10 Sialylation of IgG-Fc Oligosaccharides
11. 8.11 Chemo-Enzymatic Synthesis of Novel IgG-Fc Glycans
12. 8.12 Restoration of Functionality to Aglycosylated IgG-Fc
13. 8.13 IgG-Fab Glycosylation
14. 8.14 Conclusion
15. References
Chapter 9: Bioinformatics Tools for Analysis of Antibodies
1. 9.1 Introduction
2. 9.2 Numbering Schemes for Antibodies
3. 9.3 Definition of the CDRs and Related Regions
4. 9.4 Antibody Sequence Data
5. 9.5 Antibody Structure Data
6. 9.6 Screening New Antibody Sequences
7. 9.7 abYsis – An Integrated Antibody Sequence and Structure Resource
8. 9.8 Antibody Structure Prediction
9. 9.9 Sequence Families
10. 9.10 Summary
11. References
12. Websites
Chapter 10: How to Use IMGT® for Therapeutic Antibody Engineering
1. 10.1 Introduction
2. 10.2 Fundamental Information from IMGT-ONTOLOGY Concepts
3. 10.3 IMGT^® Tools and Databases
4. 10.4 Examples of IMGT^® Web Resources for Antibody Engineering and Humanization
5. 10.5 Conclusions
6. Acknowledgments
7. Abbreviations
8. References
9. Website

Part II: Modified Antibodies

Chapter 11: Bispecific Antibodies
1. 11.1 Introduction
2. 11.2 The Generation of Bispecific Antibodies
3. 11.3 Bispecific Antibodies and Retargeting of Effector Cells
4. 11.4 Bispecific Antibodies and Retargeting of Effector Molecules
5. 11.5 Dual Targeting Strategies with Bispecific Antibodies
6. 11.6 Bispecific Antibodies and Somatic Gene Therapy
7. 11.7 Outlook Update
8. References
Chapter 12: Single-Domain Antibodies: An Overview
1. 12.1 Introduction
2. 12.2 Historical Perspective
3. 12.3 How are sdAbs Isolated?
4. 12.4 Target Space
5. 12.5 Bi-specifics and Targeted Payloads
6. 12.6 Pharmacokinetics/Biodistribution and Half-Life Extension Technologies
7. 12.7 Imaging
8. 12.8 Outlook
9. Acknowledgments
10. References
Chapter 13: Antibody–Drug Conjugates: New Frontier in Cancer Therapeutics
1. 13.1 Introduction
2. 13.2 Currently Approved ADCs for Cancer Treatment
3. 13.3 Cytotoxic Compounds in ADCs
4. 13.4 Linkers in ADCs
5. 13.5 Antibody in ADCs
6. 13.6 Conclusions
7. References
Chapter 14: Antibody-Targeted Drugs: From Chemical Immunoconjugates to Recombinant Fusion Proteins
1. 14.1 Introduction
2. 14.2 Lessons Learned from Chemical Immunoconjugates
3. 14.3 Recombinant Cytotoxic Fusion Proteins
4. References

Part III: Emerging Technologies

Chapter 15: Emerging Technologies for Antibody Selection
1. 15.1 Introduction
2. 15.2 Display Technologies
3. 15.3 Antibody Libraries
4. 15.4 Antibody Selection and Maturation In vitro
5. 15.5 Linking Antibodies to mRNA: Ribosome and mRNA Display
6. 15.6 Advantages of Ribosome Display
7. 15.7 Ribosome Display Systems
8. 15.8 Antibody Generation by Ribosome Display
9. 15.9 Summary
10. References
Chapter 16: Anti-Idiotypic Antibodies
1. 16.1 Introduction
2. 16.2 Basic Concepts
3. 16.3 Physiological Role of Anti-idiotypic Antibodies
4. 16.4 Anti-Idiotypic Antibody Responses
5. 16.5 Anti-Idiotypic Antibodies in Cancer
6. 16.6 Anti-idiotypic Antibodies in Other Diseases
7. 16.7 Concluding Remarks
8. References
Chapter 17: Non-Antibody Scaffolds as Alternative Therapeutic Agents
1. 17.1 Introduction
2. 17.2 Motivation for Therapeutic Use of Alternative Binding Proteins
3. 17.3 Single Domain Immunoglobulins
4. 17.4 Scaffold Proteins Presenting a Contiguous Hypervariable Loop Region
5. 17.5 Scaffold Proteins for Display of Individual Extended Loops
6. 17.6 Scaffold Proteins Providing a Rigid Secondary Structure Interface
7. 17.7 Non-Antibody Scaffolds Stepping into the Clinic
8. 17.8 Conclusions and Outlook: Therapeutic Potential and Ongoing Developments
9. References
Chapter 18: Antibody-Directed Enzyme Prodrug Therapy (ADEPT)
1. 18.1 Introduction and Basic Principles of ADEPT
2. 18.2 Pre-clinical Studies
3. 18.3 Clinical Studies
4. 18.4 Immunogenicity
5. 18.5 Important Considerations/Outlook
6. Acknowledgments
7. Abbreviations
8. References
Chapter 19: Engineered Antibody Domains as Candidate Therapeutics
1. 19.1 Introduction
2. 19.2 eAd Structure and Function
3. 19.3 eAd Libraries
4. 19.4 eAds against HIV-1
5. 19.5 eAds Targeting Cancer
6. 19.6 eAds against Inflammation
7. 19.7 eAds against Hematological Disorders
8. 19.8 Conclusions
9. Acknowledgments
10. References
Chapter 20: Chimeric Antigen Receptors – “CARs”
1. 20.1 Introduction
2. 20.2 Chimeric Antigen Receptors – “CARs”
3. 20.3 Preclinical Studies
4. 20.4 Therapeutic Considerations
5. 20.5 Perspectives
6. 20.6 Conclusions
7. References
Chapter 21: Emerging Alternative Production Systems
1. 21.1 Introduction
2. 21.2 Production Systems
3. 21.3 Outlook
4. Abbreviations
5. References

Volume II: Clinical Development of Antibodies

Part IV: The Way into the Clinic

Chapter 22: Process Development and Manufacturing of Therapeutic Antibodies
1. 22.1 Introduction
2. 22.2 Upstream Processing
3. 22.3 Downstream Processing
4. 22.4 Formulation Development
5. 22.5 Commercial Manufacturing Processes
6. 22.6 Analytics
7. 22.7 Overall Process Development Strategies and Outlook
8. Acknowledgments
9. References
Chapter 23: The Immunogenicity of Therapeutic Antibodies
1. 23.1 Introduction
2. 23.2 Immunogenicity and the Immune System
3. 23.3 Factors Influencing Immunogenicity
4. 23.4 Clinical Consequences of Immunogenicity of Abs
5. 23.5 Bioanalytical Assessment of ADAs against Therapeutic Antibodies
6. 23.6 Immunogenicity Prediction Tools
7. 23.7 Reduction of Immunogenicity of Abs
8. 23.8 A Look into the Future – The Rise of Antibody-Based Drugs
9. 23.9 Conclusions
10. References
Chapter 24: Biosimilar Monoclonal Antibodies
1. 24.1 Introduction
2. 24.2 EU Approach to Biosimilars
3. 24.3 US Biosimilars
4. 24.4 Follow-On Monoclonal Antibodies in Emerging Markets
5. 24.5 Technical Development and Analytical Characterization of Biosimilar Monoclonal Antibodies
6. 24.6 Non-Clinical and Clinical Development of Biosimilar Monoclonal Antibodies/Pharmacovigilance and Risk Management
7. Acknowledgments
8. Abbreviations
9. References
Chapter 25: Patent Issues Relating to Therapeutic Antibodies
1. 25.1 Why Patents Matter
2. 25.2 Types of Patent Protection in the Field of Therapeutic Antibodies
3. 25.3 Freedom to Operate
4. 25.4 Protecting New Developments
5. 25.5 Management of Own and Third-Party Patents
6. 25.6 Patent Exploitation Options and Business Models
7. 25.7 Outlook
8. 25.8 Reference Materials and Further Reading

Part V: Therapeutic Antibody Pipeline

Chapter 26: Monoclonal Antibody Cancer Treatments in Phase III Clinical Trials
1. 26.1 Introduction
2. 26.2 Antibodies for Use in Lymphoma and Related Diseases
3. 26.3 Anti-EpCAM Antibodies: A Lesson in History and What Remains
4. 26.4 Antibodies Against Epithelial Growth Factor Targets
5. 26.5 Insulin-Like Growth Factor Type I Receptor Antibodies
6. 26.6 Antibodies for Use in Renal Cell Carcinoma
7. 26.7 Antibodies for Use in Ovarian Cancer
8. 26.8 Blockage of Immunological Checkpoints
9. 26.9 Miscellaneous Diseases and Targets
10. 26.10 Summary
11. References
Chapter 27: Antibodies in Cancer Treatment: Early Clinical Development
1. 27.1 Introduction
2. 27.2 Harnessing Innate Immunity
3. 27.3 Alteration of Intracellular Signaling
4. 27.4 Immunoconjugates
5. 27.5 The Three U's: Mechanisms of Unique, Unclear, or Unknown Function
6. 27.6 Summary
7. References
Chapter 28: Targeting Angiogenesis by Therapeutic Antibodies
1. 28.1 Introduction
2. 28.2 Therapeutic Antibodies
3. 28.3 Conclusion
4. Abbreviations
5. References
Chapter 29: Antibodies in Phase III Studies for Immunological Disorders
1. 29.1 Introduction
2. 29.2 Antibody Targets in Phase III Trials
3. 29.3 Summary
4. References
Chapter 30: Monoclonal Antibodies in Phase 1 and 2 Studies for Immunological Disorders
1. 30.1 Introduction
2. 30.2 General Overview of the Immune System and Key Pathways Driving Inflammatory Diseases
3. 30.3 Review of the Major Inflammatory Diseases Targeted by mAbs, Goals of Current Therapies and How These Might Be Met by Existing and Emerging Biologics
4. 30.4 Mechanisms of Target Modulation Utilized by Monoclonal Antibodies
5. 30.5 Optimizing mAbs for Efficacy and Safety
6. 30.6 Summary
7. References
Chapter 31: MAbs Targeting Soluble Mediators in Phase 1 and 2 Clinical Studies Immunological Disorders
1. 31.1 Introduction
2. References
Chapter 32: T Cell Inhibitors in Phase 1 and 2 Clinical Studies for Immunological Disorders
1. 32.1 Introduction
2. 32.2 T-Cell Inhibitors
3. 32.3 Anti-T-Cell Costimulators
4. References
Chapter 33: B-Cell Inhibitors in Phase 1 and 2 Clinical Studies for Immunological Disorders
1. 33.1 Introduction
2. 33.2 Anti-CD19
3. 33.3 Anti-BAFF (Blys)
4. 33.4 Anti-CD20
5. References
Chapter 34: Inhibitors of Leukocyte Adhesion and Migration in Phase 1 and 2 Clinical Studies for Immunological Disorders
1. 34.1 Introduction
2. 34.2 Inhibitors of Leukocyte Adhesion and Migration
3. References
Chapter 35: Toll-Like Receptor Inhibitors in Phase 1 and 2 Clinical Studies for Immunological Disorders
1. 35.1 Introduction
2. 35.2 Toll-Like Receptor Inhibitors
3. References
Chapter 36: IgE Inhibitors in Phase 1 and 2 Clinical Studies for Immunological Disorders
1. 36.1 Introduction
2. 36.2 IgE Inhibitors
3. References
Chapter 37: Complement Inhibitors in Phase 1 and 2 Clinical Studies for Immunological Disorders
1. 37.1 Introduction
2. 37.2 Complement Inhibitors
3. References
Chapter 38: mAbs Targeting Apoptosis, Angiogenesis Inhibitors, and Other mAbs in Phase 1 and 2 Clinical Studies for Immunological Disorders
1. 38.1 mAbs Targeting Apoptosis
2. 38.2 Angiogenesis Inhibitors
3. 38.3 Other mAbs
4. References
Chapter 39: In vitro Studies and Clinical Trials about Monoclonal Antibodies Used in Infectiology
1. 39.1 Introduction and Infectious Context
2. 39.2 Historical of Antibodies Used in Infectiology and Previous Clinical Trials
3. 39.3 General Mechanisms of Action
4. 39.4 Mode of Production of Anti-Infectious Antibodies
5. 39.5 Anti-Infectious Monoclonal Antibodies Against Bacteria and Associated Toxins
6. 39.6 Viral Diseases and Anti-Infectious Monoclonal Antibodies
7. 39.7 Perspectives and Future Development of Antimycotic Monoclonal Antibodies
8. 39.8 Conclusion
9. Acknowledgments
10. Author Contributions
11. Funding
12. Transparency Declarations Sections and Conflicts of Interest
13. References
Chapter 40: Immunotherapeutics for Neurological Disorders
1. 40.1 Introduction
2. 40.2 Alzheimer's Disease
3. 40.3 Parkinson's Disease and Dementia with Lewy Bodies
4. 40.4 Huntington's Disease
5. 40.5 Amyotrophic Lateral Sclerosis
6. 40.6 Transmissible Spongiform Encephalopathies
7. 40.7 Conclusion
8. Acknowledgments
9. References

Part VI: Gaining Marketing Approval

Chapter 41: Regulatory Considerations in the Development of Monoclonal Antibodies for Diagnosis and Therapy*
1. 41.1 Introduction
2. 41.2 Regulatory Authority
3. 41.3 Chemistry, Manufacturing, and Controls Considerations
4. 41.4 Considerations for Nonclinical Testing
5. 41.5 Immunogenicity
6. 41.6 Conclusions
7. Acknowledgments
8. References
Chapter 42: Regulatory Review: Clinical to Market Transition
1. 42.1 Introduction
2. 42.2 General Considerations for the Clinical Development of mAbs
3. 42.3 The Need for Regulatory Validation of the Development Program
4. 42.4 The Approach of Agencies for Clinical Review of mAb
5. 42.5 Strategic Regulatory Options for Rapid Market Access
6. 42.6 Pivotal Clinical Trials for mAb
7. 42.7 Specific Considerations for Early Development Clinic Studies of mAb
8. References
Chapter 43: Monoclonal Antibody Nomenclature for Clinical Studies (USA)1
1. 43.1 Elements of a Name
2. 43.2 Sequence of Stems and Infixes
3. 43.3 Target/Disease Class Infix
4. 43.4 USAN Modified Designations for Monoclonal Antibodies
5. 43.5 Required Application Information

Volume III: Approved Therapeutic Antibodies

Part VII: Approved Therapeutic Antibodies

Chapter 44: Oligoclonal and Polyclonal Antibody Preparations
1. 44.1 Introduction
2. 44.2 Oligoclonal Antibodies
3. 44.3 General Questions/Concerns
4. 44.4 Uses/Applications of Oligoclonal Antibodies
5. 44.5 Infectious Disease
6. 44.6 FDA/Regulatory Considerations
7. 44.7 Polyclonal Antibodies
8. 44.8 Production of Polyclonal Antibodies
9. 44.9 Immunogen Properties and Preparations
10. 44.10 Carrier Proteins for Immunogen Preparation
11. 44.11 Choice of Animal
12. 44.12 Adjuvants
13. 44.13 Route of Injection
14. 44.14 Collecting and Processing of Blood
15. 44.15 Antibody Purification
16. 44.16 Polyclonal Antibody Derives Therapeutics (Clinical Utility)
17. 44.17 Recombinant Polyclonal Antibodies
18. 44.18 Summary
19. References
Chapter 45: Adalimumab (Humira®)
1. 45.1 Overview
2. 45.2 Basic Principles of Clinical Use
3. 45.3 Safety
4. 45.4 Use in Approved Indications
5. 45.5 Clinical Studies in Intestinal Behçet Disease
6. 45.6 Clinical Studies in Uveitis
7. 45.7 Clinical Studies in Hidradenitis Suppurativa
8. 45.8 Early-Stage Clinical Studies in Sarcoidosis
9. References
Chapter 46: Alemtuzumab (Lemtrada, MabCampath)1
1. 46.1 Overview
2. 46.2 Basic Principles
3. 46.3 Antibody Features and Production
4. 46.4 Molecular Target and Target Expression
5. 46.5 Mechanism of Cell Lysis
6. 46.6 Immunogenicity and Antiglobulin Response
7. 46.7 Pharmacokinetic Studies
8. 46.8 Clinical Studies in Chronic Lymphocytic Leukemia (CLL)
9. 46.9 Clinical Studies in Multiple Sclerosis
10. 46.10 Clinical Studies in Other Indications
11. References
Chapter 47: Basiliximab (Simulect®) and Daclizumab (Zenapax®)
1. 47.1 Background
2. 47.2 Clinical Use in Human Organ Transplantation
3. 47.3 Clinical Use of IL-2R Antibodies in Non-organ Transplant Conditions
4. 47.4 Conclusion
5. References
Chapter 48: Belimumab (Benlysta®)
1. 48.1 Introduction
2. 48.2 Basic Principles
3. 48.3 Clinical Aspects of Belimumab Therapy
4. 48.4 Summary
5. List of abbreviations
6. References
Chapter 49: Brentuximab Vedotin (Adcetris®) for the Treatment of CD30-Positive Hematologic Malignancies
1. 49.1 Introduction
2. 49.2 CD30
3. 49.3 Preclinical Activity of Brentuximab Vedotin
4. 49.4 Clinical Development of Brentuximab Vedotin
5. 49.5 Future Perspectives
6. Acknowledgments
7. References
Chapter 50: Canakinumab (ILARIS®)
1. 50.1 Introduction
2. 50.2 Production, Pharmacology, and Pharmacokinetics of Canakinumab
3. 50.3 Clinical Trials
4. 50.4 Outlook and Summary
5. References
Chapter 51: Catumaxomab (Removab) – Trifunctional Antibodies: Combining Direct Tumor Cell Killing with Therapeutic Vaccination
1. 51.1 Introduction
2. 51.2 Manufacturing of trAbs
3. 51.3 The Mode of Action of trAbs in Tumor Treatment
4. 51.4 From Bench to Bedside with the Triomab^® trAb Family
5. 51.5 Potential Biomarkers Along trAb Treatment Concept
6. 51.6 Concluding Remarks
7. Acknowledgments
8. References
Chapter 52: Cetuximab (Erbitux)
1. 52.1 Nature, Role in Disease, Biology of the Target
2. 52.2 Origin and Development of Erbitux
3. 52.3 Mechanism of Action
4. 52.4 Preclinical and Clinical Results
5. 52.5 Production
6. 52.6 Cetuximab in Clinics
7. 52.7 Outlook
8. References
9. Websites
Chapter 53: Denosumab (Prolia^®)
1. 53.1 Introduction
2. 53.2 Clinical Studies
3. 53.3 Guidelines of the FDA (Website of FDA) for Denosumab (Prolia)
4. 53.4 Summary and Outlook
5. References
6. Websites
Chapter 54: Efalizumab (Raptiva)
1. 54.1 Introduction
2. 54.2 Development and Characterization of the Antibody
3. 54.3 Efalizumab in the Treatment of Psoriasis
4. 54.4 Pharmacology and Toxicology of Efalizumab
5. 54.5 Clinical Development of Efalizumab
6. 54.6 Health-Related Quality of Life (HRQoL)
7. 54.7 Safety and Tolerability
8. 54.8 Efalizumab: Reassessment of Benefit–Risk Ratio and Suspension of Marketing Authorization
9. References
Chapter 55: Calicheamicin Conjugates: Gemtuzumab Ozogamicin (Mylotarg), Inotuzumab Ozogamicin
1. 55.1 Introduction
2. 55.2 Target Antigen Selection in Therapy with ADC
3. 55.3 Conjugate Design/Preclinical Activity
4. 55.4 Mechanisms of Action
5. 55.5 Potential Mechanisms of Resistance
6. 55.6 Clinical Trials
7. 55.7 Summary and Conclusions
8. References
Chapter 56: Golimumab (Simponi®)
1. 56.1 Introduction
2. 56.2 Characterization and Preclinical Evaluation
3. 56.3 First-in-Humans Study
4. 56.4 Pivotal Clinical Studies
5. 56.5 Market Competitors
6. References
Chapter 57: Yttrium-90 Ibritumomab Tiuxetan (Zevalin^®)
1. 57.1 Introduction
2. 57.2 Basic Principles of Radioimmunotherapy
3. 57.3 Development and Advantages of ⁹⁰Y-Ibritumomab Tiuxetan
4. 57.4 Preclinical and Clinical Results
5. 57.5 Outlook
6. References
Chapter 58: Infliximab (Remicade®)
1. 58.1 Antibody Characteristics
2. 58.2 Preclinical Characterization
3. 58.3 Pharmacokinetics
4. 58.4 Clinical Response
5. 58.5 Safety
6. 58.6 Summary
7. References
Chapter 59: Ipilimumab (Yervoy®)
1. 59.1 Introduction
2. 59.2 Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4)
3. 59.3 Ipilimumab, Mechanism of Action
4. 59.4 Pharmacokinetics
5. 59.5 Melanoma
6. 59.6 Prostate Cancer
7. 59.7 Lung Cancer
8. 59.8 Patterns of Response with Ipilimumab (Immune-Related Response Criteria)
9. 59.9 Adverse Events
10. 59.10 Conclusions
11. References
Chapter 60: Muromonab-CD3 (Orthoclone OKT®3)
1. 60.1 Introduction
2. 60.2 Production of mAbs
3. 60.3 Pharmacology of Muromonab-CD3
4. 60.4 Therapeutic Use
5. 60.5 Cytokine Release Syndrome
6. 60.6 Consequences of Immunosuppression
7. 60.7 Withdrawal from the Market
8. References
Chapter 61: Nimotuzumab: A Humanized Anti-EGFR Antibody
1. 61.1 Overview
2. 61.2 Head and Neck
3. 61.3 Glioma
4. 61.4 Pediatric Glioma
5. 61.5 Esophageal and Gastric Cancer
6. 61.6 Pancreatic Cancer
7. 61.7 Non-Small Cell Lung Cancer (NSCLC)
8. 61.8 Concluding Remarks
9. References
Chapter 62: Obinutuzumab (Gazyva®), a Novel Glycoengineered Type II CD20 Antibody for the Treatment of Chronic Lymphocytic Leukemia and Non-Hodgkin's Lymphoma
1. 62.1 In vitro Mechanism of Action of Type I and Type II CD20 Antibodies
2. 62.2 Generation of Obinutuzumab
3. 62.3 Obinutuzumab is a Classical Type II CD20 Antibody
4. 62.4 The Epitope Recognized by Obinutuzumab
5. 62.5 CDC Activity of Obinutuzumab
6. 62.6 Direct Cell Death Induction by Obinutuzumab
7. 62.7 Glycoengineering of Obinutuzumab
8. 62.8 In vitro NK Cell and Neutrophil ADCC and Macrophage ADCP Activity of Obinutuzumab
9. 62.9 Ex vivo Whole Blood B-Cell Depletion by Obinutuzumab
10. 62.10 In vivo Activity of Obinutuzumab in Xenograft Models
11. 62.11 In vivo Activity of Obinutuzumab in Combination with Chemotherapy, Bcl-2, and MDM2 Inhibitors
12. 62.12 B-Cell Depletion by Obinutuzumab in Cynomolgus Monkeys
13. 62.13 Conclusion from Nonclinical Pharmacology Studies with Obinutuzumab
14. 62.14 Clinical Experiences with Obinutuzumab
15. 62.15 Early Clinical Experience with Obinutuzumab in B-Cell Lymphoma
16. 62.16 Phase Ib and II Experience with Obinutuzumab in B-Cell Lymphoma
17. 62.17 Phase III Studies with Obinutuzumab in B-Cell Lymphoma
18. 62.18 Obinutuzumab in CLL: Early Experience and Ongoing Phase II Studies
19. 62.19 Phase III Experience with Obinutuzumab: The CLL11 Trial
20. References

Volume IV: Approved Therapeutic Antibodies and in vivo Diagnostics

Chapter 63: Ofatumumab (Arzerra®): a Next-Generation Human Therapeutic CD20 Antibody with Potent Complement-Dependent Cytotoxicity
1. 63.1 Introduction and Preliminary Comments
2. 63.2 Physical and Immunochemical Characteristics of OFA Compared to RTX
3. 63.3 Functional Characterizations
4. 63.4 CD20: It Is certainly a Good Target, but How Well Characterized Is It?
5. 63.5 Key Results of Clinical Trials with OFA
6. 63.6 Summary and Future Directions
7. Abbreviations
8. 63.7 Disclosures
9. References
Chapter 64: Omalizumab (Xolair) – Anti-Immunoglobulin E Treatment in Allergic Diseases
1. 64.1 Introduction
2. 64.2 The Biology of the IgE Molecule
3. 64.3 IgE Receptors
4. 64.4 Cell Distribution of IgE
5. 64.5 Physiologic and Pathophysiologic Significance of IgE
6. 64.6 The Concept of Anti-IgE-Based Treatment
7. 64.7 Construction of the Monoclonal Anti-IgE Molecule
8. 64.8 Efficacy
9. 64.9 Anti-Inflammatory Effects of Omalizumab
10. 64.10 Pharmacological Properties of Omalizumab
11. 64.11 Adverse Effects
12. 64.12 Indications
13. 64.13 Contraindications
14. 64.14 Preparation for Use
15. 64.15 Administration
16. 64.16 Dosing of Omalizumab
17. 64.17 Response to Treatment
18. 64.18 Assessment of Therapeutic Response
19. 64.19 Monitoring of Therapy
20. 64.20 Drug Interactions
21. 64.21 Pregnancy and Lactation
22. 64.22 Cost
23. 64.23 Non-approved Diseases
24. 64.24 Conclusions
25. Acknowledgments
26. References
27. Websites
Chapter 65: Palivizumab (Synagis®)
1. 65.1 Nature, Role in Disease, and Biology of the Target
2. 65.2 Origin, Engineering, and Humanization of the Antibody
3. 65.3 Mechanism of Action and Preclinical Results
4. 65.4 Production, Downstream Processing, and Galenics of the Antibody
5. 65.5 Summary of Results from Clinical Studies
6. 65.6 Indications and Usage
7. 65.7 Clinical Reports after Approval
8. 65.8 Protective Efficacy as a Function of Palivizumab Serum Concentration?
9. 65.9 Postmarketing Experience with Regard to Adverse Events (AEs)
10. 65.10 Toward Improved Versions of Palivizumab
11. 65.11 Summary
12. Acknowledgments
13. Abbreviations
14. References
Chapter 66: Panitumumab (Vectibix®): A Treatment for Metastatic Colorectal Cancer
1. 66.1 Introduction
2. 66.2 Panitumumab (Vectibix)
3. 66.3 Results from Clinical Studies
4. 66.4 Summary and Outlook
5. References
Chapter 67: Pertuzumab (Perjeta®)
1. 67.1 HER2-Positive Breast Cancer
2. 67.2 Mechanisms of Trastuzumab Resistance
3. 67.3 Preclinical Development
4. 67.4 Pertuzumab Clinical Development
5. 67.5 Pertuzumab Cardiac Safety Profile
6. References
Chapter 68: Ranibizumab (Lucentis): a New Anti-Angiogenic Treatment in Ophthalmology
1. 68.1 Introduction
2. 68.2 Ranibizumab: Clinical Studies in Retinal Disorders
3. 68.3 Other Molecules with Anti-VEGF Effect of Clinical Use in Retinal Disorders
4. References
Chapter 69: Raxibacumab, Human Monoclonal Antibody against Anthrax Toxin
1. 69.1 Introduction
2. 69.2 Development of Raxibacumab
3. 69.3 Demonstration of Effectiveness under the Animal Rule
4. 69.4 Safety
5. 69.5 Dosing
6. 69.6 Indication
7. 69.7 Conclusion
8. Abbreviations
9. References
Chapter 70: Rituximab (Rituxan®)
1. 70.1 Introduction
2. 70.2 Rituximab Clinical Data in B-Cell Lymphoma
3. 70.3 Rituximab in Autoimmune Disorders
4. 70.4 Development of a Subcutaneous Rituximab Formulation (Rituximab SC) in B-Cell Lymphoma and CLL
5. 70.5 Summary and Conclusions
6. References
7. Websites
Chapter 71: Tocilizumab (Actemra®)
1. 71.1 Introduction
2. 71.2 Biological Activities and Signaling of IL-6
3. 71.3 Targeting IL-6 with Monoclonal Antibodies
4. 71.4 Targeting IL-6 in Rheumatoid Arthritis
5. 71.5 Targeting IL-6 in Systemic-Onset Juvenile Idiopathic Arthritis
6. 71.6 Targeting IL-6 in Castleman's Disease
7. 71.7 Other Indications
8. 71.8 Adverse Events Associated with Targeting the IL-6 Receptor
9. 71.9 Current State of Play
10. References
Chapter 72: Trastuzumab (Herceptin®) and Ado-Trastuzumab Emtansine (Kadcyla®): Treatments for HER2-Positive Breast Cancer
1. 72.1 Introduction
2. 72.2 Metastatic Breast Cancer
3. 72.3 Early Breast Cancer
4. 72.4 Cardiac Adverse Events
5. 72.5 Infusion-Related Reactions
6. 72.6 Age Considerations
7. 72.7 Patient Considerations
8. 72.8 Dosing/Scheduling
9. 72.9 Ado-Trastuzumab Emtansine (T-DM1), Trade Name Kadcyla
10. 72.10 Safety and Side Effects
11. 72.11 FDA Approval
12. 72.12 Conclusions
13. References
Chapter 73: Ustekinumab (Stelara®)
1. 73.1 Introduction
2. 73.2 Psoriasis
3. 73.3 Psoriatic Arthritis
4. 73.4 Crohn's Disease
5. 73.5 Multiple Sclerosis
6. 73.6 Meta Analyses on Long-Term Use
7. 73.7 Ongoing Studies, New Indications, and Outlook
8. References
Chapter 74: Abciximab (Reopro®), Bevacizumab (Avastin®), Certolizumab Pegol (Cimzia®), Eculizumab (Soliris®), Natalizumab (Tysabri®)
1. 74.1 Abciximab (Reopro)
2. 74.2 Bevacizumab (Avastin)
3. 74.3 Certolizumab Pegol (Cimzia)
4. 74.4 Eculizumab (Soliris)
5. 74.5 Natalizumab (Tysabri)
6. References
Chapter 75: Itolizumab (Alzumab®), Mogamulizumab (Poteligeo®), and Tositumomab (Bexxar®)
1. 75.1 Itolizumab (Alzumab)
2. 75.2 Mogamulizumab (Poteligeo)
3. 75.3 Tositumomab; Iodine ¹³¹I Tositumomab (Bexxar)
4. References
5. Further Reading
6. Information Sources

Part VIII: In vivo Diagnostics

Chapter 76: Radiolabeled Antibodies for Diagnostic Imaging
1. 76.1 Introduction
2. 76.2 Oncology
3. 76.3 Cardiology
4. 76.4 Infection
5. 76.5 Summary
6. References
Index

End User License Agreement

List of Illustrations

Figure 1.1

Figure 1.2

Figure 1.3

Figure 2.1

Figure 2.2

Figure 2.3

Figure 2.4

Figure 2.5

Figure 2.6

Figure 2.7

Figure 3.1

Figure 4.1

Figure 4.2

Figure 4.3

Figure 4.4

Figure 4.5

Figure 4.6

Figure 4.7

Figure 5.1

Figure 6.1

Figure 6.2

Figure 6.3

Figure 6.4

Figure 7.1

Figure 7.2

Figure 7.3

Figure 8.1

Figure 8.2

Figure 8.3

Figure 10.1

Figure 10.2

Figure 10.3

Figure 10.4

Figure 10.5

Figure 10.6

Figure 10.7

Figure 10.8

Figure 10.9

Figure 10.10

Figure 11.1

Figure 11.2

Figure 11.3

Figure 11.4

Figure 11.5

Figure 11.6

Figure 11.7

Figure 11.8

Figure 11.9

Figure 11.10

Figure 12.1

Figure 12.2

Figure 12.3

Figure 12.4

Figure 13.1

Figure 13.2

Figure 13.3

Figure 13.4

Figure 13.5

Figure 15.1

Figure 15.2

Figure 15.3

Figure 16.1

Figure 16.2

Figure 17.1

Figure 17.2

Figure 18.1

Figure 19.1

Figure 19.2

Figure 19.3

Figure 19.4

Figure 20.1

Figure 20.2

Figure 20.3

Figure 20.4

Figure 22.1

Figure 22.2

Figure 22.3

Figure 22.4

Figure 22.5

Figure 22.6

Figure 22.7

Figure 22.8

Figure 22.9

Figure 22.10

Figure 22.11

Figure 22.12

Figure 22.13

Figure 23.1

Figure 23.2

Figure 23.3

Figure 24.1

Figure 24.2

Figure 24.3

Figure 24.4

Figure 24.5

Figure 24.6

Figure 24.7

Figure 25.1

Figure 16.1

Figure 28.1

Figure 28.2

Figure 41.1

Figure 46.1

Figure 46.2

Figure 46.3

Figure 46.4

Figure 46.5

Figure 46.6

Figure 46.7

Figure 46.8

Figure 49.1

Figure 49.2

Figure 49.3

Figure 49.4

Figure 50.1

Figure 50.2

Figure 50.3

Figure 50.4

Figure 50.5

Figure 51.1

Figure 51.2

Figure 51.3

Figure 51.4

Figure 51.5

Figure 51.6

Figure 52.1

Figure 53.1

Figure 55.1

Figure 55.2

Figure 55.3

Figure 55.4

Figure 57.1

Figure 57.2

Figure 59.1

Figure 60.1

Figure 62.1

Figure 62.2

Figure 62.3

Figure 62.4

Figure 63.1

Figure 63.2

Figure 63.3

Figure 63.4

Figure 63.5

Figure 63.6

Figure 63.7

Figure 63.8

Figure 63.9

Figure 63.10

Figure 64.1

Figure 64.2

Figure 64.3

Figure 64.4

Figure 64.5

Figure 64.6

Figure 64.7

Figure 64.8

Figure 64.9

Figure 64.10

Figure 64.11

Figure 64.12

Figure 64.13

Figure 64.14

Figure 64.15

Figure 64.16

Figure 64.17

Figure 65.1

Figure 65.2

Figure 65.3

Figure 65.4

Figure 65.5

Figure 66.1

Figure 68.1

Figure 68.2

Figure 68.3

Figure 68.4

Figure 70.1

Figure 70.2

Figure 70.3

Figure 70.4

Figure 70.5

Figure 70.6

Figure 70.7

Figure 70.8

Figure 70.9

Figure 70.10

Figure 70.11

Figure 70.12

Figure 70.13

Figure 72.1

Figure 72.2

Figure 72.3

Figure 72.4

Figure 72.5

Figure 72.6

Figure 72.7

Figure 72.9

Figure 72.8

Figure 72.10

Figure 72.11

Figure 73.1

Figure 76.1

Figure 76.2

Figure 76.3

Figure 76.4

Figure 76.5

Figure 76.6

Figure 76.7

Figure 76.8

Figure 76.9

List of Tables

Table 1.1

Table 1.2

Table 2.1

Table 3.1

Table 3.2

Table 3.3

Table 5.1

Table 5.2

Table 7.2

Table 7.1

Table 7.3

Table 9.1

Table 9.2

Table 9.3

Table 9.4

Table 9.5

Table 10.1

Table 10.2

Table 10.3

Table 11.1

Table 11.2

Table 12.1

Table 12.2

Table 13.1

Table 13.2

Table 14.1

Table 14.2

Table 14.3

Table 15.1

Table 17.1

Table 17.2

Table 17.3

Table 17.4

Table 19.1

Table 20.1

Table 20.2

Table 20.3

Table 20.4

Table 21.1

Table 22.1

Table 22.2

Table 22.3

Table 22.4

Table 22.5

Table 22.6

Table 22.7

Table 22.8

Table 23.1

Table 23.2

Table 23.3

Table 23.4

Table 23.5

Table 24.1

Table 24.2

Table 26.1

Table 29.1

Table 29.2

Table 29.3

Table 29.4

Table 29.5

Table 29.6

Table 29.7

Table 29.8

Table 29.9

Table 29.10

Table 29.11

Table 29.12

Table 30.1

Table 30.2

Table 41.1

Table 41.2

Table 42.1

Table 42.2

Table 44.1

Table 44.2

Table 45.1

Table 46.1

Table 46.2

Table 46.3

Table 46.4

Table 46.5

Table 46.6

Table 46.7

Table 47.1

Table 47.2

Table 47.3

Table 48.1

Table 49.1

Table 49.2

Table 51.1

Table 51.2

Table 51.3

Table 51.4

Table 52.1

Table 52.2

Table 53.1

Table 56.1

Table 57.1

Table 57.2

Table 57.3

Table 57.4

Table 59.1

Table 59.2

Table 59.3

Table 59.4

Table 60.1

Table 60.2

Table 60.3

Table 60.4

Table 60.5

Table 62.1

Table 62.2

Table 62.3

Table 63.1

Table 63.2

Table 64.1

Table 64.2

Table 64.3

Table 64.4

Table 64.5

Table 64.6

Table 64.7

Table 64.8

Table 64.9

Table 64.10

Table 64.11

Table 65.1

Table 65.2

Table 65.3

Table 66.1

Table 67.1

Table 69.1

Table 70.1

Table 70.2

Table 70.3

Table 70.4

Table 70.5

Table 70.6

Table 70.7

Table 70.8

Table 71.1

Table 71.2

Table 71.3

Table 72.1

Table 72.2

Table 72.3

Table 73.1

Related Titles

Chamow, S.M., Ryll, T., Lowman, H.B., Farson, D. (eds.)

Therapeutic Fc-Fusion Proteins

2014

Print ISBN: 978-3-527-33317-2, also available in digital formats

Knäblein, J. (ed.)

Modern Biopharmaceuticals

Recent Success Stories

2013

Print ISBN: 978-3-527-32283-1, also available in digital formats

Pathak, Y., Benita, S. (eds.)

Antibody-Mediated Drug Delivery Systems

Concepts, Technology, and Applications

2012

Print ISBN: 978-0-470-61281-1, also available in digital formats

Kratz, F., Senter, P., Steinhagen, H. (eds.)

Drug Delivery in Oncology

From Basic Research to Cancer Therapy

2011

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Tovey, M.G. (ed.)

Detection and Quantification of Antibodies to Biopharmaceuticals

Practical and Applied Considerations

2011

Print ISBN: 978-0-470-56666-4, also available in digital formats

Editors

Prof. Dr. Stefan Dübel

Technische Universität Braunschweig

Institute of Biochemistry

Biotechnology and Bioinformatics

Spielmannstr. 7

38106 Braunschweig

Germany

Dr. Janice M. Reichert

Reichert Biotechnology Consulting LLC

Prospect Street 247

Framingham, MA

USA

Cover

Antibodies have become standard therapy in many therapeutic areas including cancer, inflammation, osteoporosis, autoimmune, cardiovascular, ophthalmic and infectious diseases. Early successes in the treatment of leukemia and lymphoma by rituximab and alemtuzumab spawned the development of ofatumumab and obinutuzumab, antibodies that kill tumor cells more potently via diverse mechanisms. The cover is an artist's impression of lymphocytic leukemia cells under therapeutic antibody attack. The image was developed by Joost M. Bakker, www.scicomvisuals.com.

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty can be created or extended by sales representatives or written sales materials. The Advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

Library of Congress Card No.: applied for

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library.

Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at <http://dnb.d-nb.de>.

Wiley-Blackwell is an imprint of John Wiley & Sons, formed by the merger of Wiley's global Scientific, Technical, and Medical business with Blackwell Publishing.

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

Print ISBN: 978-3-527-32937-3

ePDF ISBN: 978-3-527-68245-4

ePub ISBN: 978-3-527-68244-7

Mobi ISBN: 978-3-527-68243-0

oBook ISBN: 978-3-527-68242-3

Quick Reference List of Antibodies by International Nonproprietary Name

International Nonproprietary Name (INN)	Brand Name	Chapter	Page

Abciximab	ReoPro	74	2087
Adalimumab	Humira	45	1309
Ado-Trastuzumab Emtansine	Kadcyla	72	2041
Alemtuzumab	Campath, Lemtrada	46	1323
Arcitumomab	CEA-Scan	76	2124
Basiliximab	Simulect	47	1375
Belimumab	Benlysta	48	1405
Besilesomab	Scintimun	76	2131
Bevacizumab	Avastin	74	2087
Brentuximab Vedotin	Adcetris	49	1417
Canakinumab	Ilaris	50	1445
Capromab In111	ProstaScint	76	2126
Catumaxomab	Removab	51	1463
Certolizumab Pegol	Cimzia	74	2087
Cetuximab	Erbitux	52	1501
Daclizumab	Zenapax	47	1375
Denosumab	Prolia	53	1521
Eculizumab	Soliris	74	2087
Efalizumab	Raptiva	54	1531
Fanolesomab	NeutroSpec	76	2132
Gemtuzumab Ozogamicin	Mylotarg	55	1545
Golimumab	Simponi	56	1565
Ibritumomab Tiuxetan	Zevalin	57	1579
Imciromab Pentetate	Myoscint	76	2129
Infliximab	Remicade	58	1599
Inotuzumab Ozogamicin	–	55	1545
Ipilimumab	Yervoy	59	1619
Itolizumab	Alzumab	75	2113
Mogamulizumab	Poteligeo	75	2113
Muromonab	Orthoclone	60	1645
Natalizumab	Tysabri	74	2087
Nimotuzumab	TheraCIM	61	1679
Obinutuzumab	Gazyva	62	1695
Ofatumumab	Arzerra	63	1733
Omalizumab	Xolair	64	1775
Palivizumab	Synagis	65	1825
Panitumumab	Vectibix	66	1855
Pertuzumab	Perjeta	67	1871
Ranibizumab	Lucentis	68	1883
Raxibacumab	–	69	1899
Rituximab	Rituxan	70	1909
Satumomab	OncoScint	76	2123
Sulesomab	Leukoscan	76	2134
Tocilizumab	Actemra	71	2023
Tositumomab Iodine131	Bexxar	75	2116
Trastuzumab	Herceptin	72	2041
Trastuzumab Emtansine	Kadcyla	72	2041
Ustekinumab	Stelara	73	2069

Quick Reference List of Antibodies by Brand Name

Brand Name	International Nonproprietary Name	Chapter	Page
Actemra	Tocilizumab	71	2023
Adcetris	Brentuximab Vedotin	49	1417
Alzumab	Itolizumab	75	2113
Arzerra	Ofatumumab	63	1733
Avastin	Bevacizumab	74	2087
Benlysta	Belimumab	48	1405
Bexxar	Tositumomab Iodine131	75	2116
Campath, Lemtrada	Alemtuzumab	46	1323
CEA-Scan	Arcitumomab	76	2124
Cimzia	Certolizumab Pegol	74	2087
Erbitux	Cetuximab	52	1501
Gazyva	Obinutuzumab	62	1695
Herceptin	Trastuzumab	72	2041
Humira	Adalimumab	45	1309
Ilaris	Canakinumab	50	1445
Kadcyla	Ado-Trastuzumab Emtansine	72	2041
Leukoscan	Sulesomab	76	2134
LeuTech	Fanolesomab	76	2132
Lucentis	Ranibizumab	68	1883
Mylotarg	Gemtuzumab Ozogamicin	55	1545
Myoscint	Imciromab Pentetate	76	2129
NeutroSpec	Fanolesomab	76	2132
OncoScint	Satumomab	76	2123
Orthoclone	Muromonab	60	1645
Perjeta	Pertuzumab	67	1871
Poteligeo	Mogamulizumab	75	2113
Prolia	Denosumab	53	1521
ProstaScint	Capromab In111	76	2126
Raptiva	Efalizumab	54	1531
Remicade	Infliximab	58	1599
Removab	Catumaxomab	51	1463
ReoPro	Abciximab	74	2087
Rituxan	Rituximab	70	1909
Scintimun	Besilesomab	76	2131
Simponi	Golimumab	56	1565
Simulect	Basiliximab	47	1375
Soliris	Eculizumab	74	2087
Stelara	Ustekinumab	73	2069
Synagis	Palivizumab	65	1825
TheraCIM	Nimotuzumab	61	1679
Tysabri	Natalizumab	74	2087
Vectibix	Panitumumab	66	1855
Xolair	Omalizumab	64	1775
Yervoy	Ipilimumab	59	1619
Zenapax	Daclizumab	47	1375
Zevalin	Ibritumomab Tiuxetan	57	1579
–	Inotuzumab Ozogamicin	55	1545
–	Raxibacumab	69	1899

A Greeting by the Editors

Today, therapeutic antibodies have matured into essential medicines for fighting cancer, inflammation, and infections, as well as other diseases. Antibody engineering now rivals classical chemistry for the generation of blockbuster drugs. The application of these therapeutic tools, which were derived from novel methods in gene technology developed between 1985 and 1995, have seen a steady and still growing expansion. Since 2006, when the first edition of the Handbook was published, the number of approved antibodies substantially increased, and novel formats like bispecifics reached the clinic in growing numbers. The importance of the advances made in the development of antibody therapeutics is underscored by the advent of biosimilar antibody products, the first of which were approved for marketing in the European Union in 2013. The field will undoubtedly continue to flourish in its third decade, driven by the expiration of many patents and ongoing maturation of technology. While new aspects have been introduced, and others silently disappeared, since the first edition of this handbook, much is left to be done. For example, new and better tumor targets are urgently needed and safety and efficacy profiles for many of the new formats must be established.

This handbook endeavours to present the fascinating story of the tremendous achievements that have been made in strengthening humanity's arsenal against widespread, as well as rare, diseases. This story not only includes the scientific and clinical basics, but covers the entire chain of therapeutic antibody research and development – from downstream processing to marketing approval and even critical intellectual property issues.

At this point, we express our deep gratitude to all our colleagues who wrote chapters for the Handbooks. Without their enthusiastic participation, this project could not have succeeded. The hard work and continuous suggestions of all these colleagues were crucial to make the idea of a comprehensive handbook on therapeutic antibodies a reality.

September 2013

Stefan Dübel and Janice Reichert

Related Titles

Handbook of Therapeutic Antibodies

Volume I: Defining the Right Antibody Composition

Handbook of Therapeutic Antibodies

Volume II: Clinical Development of Antibodies

Handbook of Therapeutic Antibodies

Volume III: Approved Therapeutic Antibodies

Handbook of Therapeutic Antibodies

Volume IV: Approved Therapeutic Antibodies and in vivo Diagnostics

Quick Reference List of Antibodies by International Nonproprietary Name

Quick Reference List of Antibodies by Brand Name

A Greeting by the Editors