Handbook of Therapeutic Antibodies

Still the most comprehensive reference source on the development, production and therapeutic application of antibodies, this second edition is thoroughly updated and now has 30% more content.

Volume 1 covers selection and engineering strategies for new antibodies, while the second volume presents novel therapeutic concepts and antibodies in clinical study, as well as their potential. Volumes 3 and 4 feature detailed and specific information about each antibody approved for therapeutic purposes, including clinical data. This unique handbook concludes with a compendium of marketed monoclonal antibodies and an extensive index.

Beyond providing current knowledge, the authors discuss emerging technologies, future developments, and intellectual property issues, such that this handbook meets the needs of academic researchers, decision makers in industry and healthcare professionals in the clinic.

• Language: English
• Publisher: Wiley
• Release date: Aug 4, 2014
• ISBN: 9783527682447

Book preview

Table of Contents

Cover

Related Titles

Title Page

Copyright

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 An Exciting Start – and a Long Trek

1.2 The Gold Rush

1.3 Success and Setbacks

1.4 The Gleaming Horizon

References

Further Reading

Part I: Selecting and Shaping the Antibody Molecule

Chapter 2: Selection Strategies for Monoclonal Antibodies

2.1 Introduction

2.2 Historical Remarks

2.3 Antibody Structure and Function

2.4 Production of Monoclonal Antibodies

2.5 Purification and Modification of Monoclonal Antibodies

2.6 Monoclonal Antibodies for Tumor Therapy

2.7 Outlook

References

Chapter 3: Antibody Phage Display

3.1 Introduction

3.2 Phage Display

3.3 Selection and Screening

3.4 Phage Display Vectors

3.5 Phage Display Libraries

3.6 Construction of Phage Display Libraries

Acknowledgments

References

Chapter 4: Transgenic Animals Derived by DNA Microinjection

4.1 Introduction

4.2 Construction of Human Ig Transloci

4.3 BAC Integration

4.4 Designer Zinc Finger Endonucleases to Silence Endogenous Ig Loci

4.5 Expression Comparison of Fully Human and Chimeric IgH Loci

4.6 Outlook

References

Chapter 5: Humanization Strategies

5.1 Introduction

5.2 History of Humanization

5.3 CDR-Grafting

5.4 The Design Cycle

5.5 Other Approaches to Antibody Humanization

References

Chapter 6: Antibody Affinity

6.1 Introduction

6.2 Affinity Maturation

6.3 Antibody Affinity: Antigen Binding and Potency

6.4 Binding and Potency In Vitro

6.5 Binding and Potency In Vivo

6.6 Selection of High-Affinity Antibodies from Hybridoma Cell Lines

6.7 Generation of Antibodies against Soluble Antigens

6.8 Generation of Antibodies against Cell Surface Antigens

6.9 Determination of Antibody Affinity

6.10 Surface Plasmon Resonance

6.11 Other Methods for Determining Antibody Affinity

6.12 Conclusion

References

Chapter 7: Fc Engineering

7.1 Mechanisms of Action of Monoclonal Antibodies

7.2 Modifying Effector Functions

7.3 Modifying Antibodies' Pharmacokinetics

7.4 Summary and Conclusions

References

Chapter 8: Glycosylation of Antibody Molecules

8.1 Introduction

8.2 Overview of the IgG Molecule

8.3 Quaternary Structure of IgG-Fc: The Protein Moiety

8.4 The IgG-Fc Oligosaccharide Moiety

8.5 IgG-Fc Protein/Oligosaccharide Interactions

8.6 Protective Mechanisms Activated by Immune Complexes

8.7 Role of IgG Glycoforms in Recognition by Cellular FγRs

8.8 The Influence of Fucose and Bisecting N-Acetylglucosamine on IgG-Fc Activities

8.9 The Influence of Galactosylation on IgG-Fc Activities

8.10 Sialylation of IgG-Fc Oligosaccharides

8.11 Chemo-Enzymatic Synthesis of Novel IgG-Fc Glycans

8.12 Restoration of Functionality to Aglycosylated IgG-Fc

8.13 IgG-Fab Glycosylation

8.14 Conclusion

References

Chapter 9: Bioinformatics Tools for Analysis of Antibodies

9.1 Introduction

9.2 Numbering Schemes for Antibodies

9.3 Definition of the CDRs and Related Regions

9.4 Antibody Sequence Data

9.5 Antibody Structure Data

9.6 Screening New Antibody Sequences

9.7 abYsis – An Integrated Antibody Sequence and Structure Resource

9.8 Antibody Structure Prediction

9.9 Sequence Families

9.10 Summary

References

Websites

Chapter 10: How to Use IMGT® for Therapeutic Antibody Engineering

10.1 Introduction

10.2 Fundamental Information from IMGT-ONTOLOGY Concepts

10.3 IMGT® Tools and Databases

10.4 Examples of IMGT® Web Resources for Antibody Engineering and Humanization

10.5 Conclusions

Acknowledgments

Abbreviations

References

Website

Part II: Modified Antibodies

Chapter 11: Bispecific Antibodies

11.1 Introduction

11.2 The Generation of Bispecific Antibodies

11.3 Bispecific Antibodies and Retargeting of Effector Cells

11.4 Bispecific Antibodies and Retargeting of Effector Molecules

11.5 Dual Targeting Strategies with Bispecific Antibodies

11.6 Bispecific Antibodies and Somatic Gene Therapy

11.7 Outlook Update

References

Chapter 12: Single-Domain Antibodies: An Overview

12.1 Introduction

12.2 Historical Perspective

12.3 How are sdAbs Isolated?

12.4 Target Space

12.5 Bi-specifics and Targeted Payloads

12.6 Pharmacokinetics/Biodistribution and Half-Life Extension Technologies

12.7 Imaging

12.8 Outlook

Acknowledgments

References

Chapter 13: Antibody–Drug Conjugates: New Frontier in Cancer Therapeutics

13.1 Introduction

13.2 Currently Approved ADCs for Cancer Treatment

13.3 Cytotoxic Compounds in ADCs

13.4 Linkers in ADCs

13.5 Antibody in ADCs

13.6 Conclusions

References

Chapter 14: Antibody-Targeted Drugs: From Chemical Immunoconjugates to Recombinant Fusion Proteins

14.1 Introduction

14.2 Lessons Learned from Chemical Immunoconjugates

14.3 Recombinant Cytotoxic Fusion Proteins

References

Part III: Emerging Technologies

Chapter 15: Emerging Technologies for Antibody Selection

15.1 Introduction

15.2 Display Technologies

15.3 Antibody Libraries

15.4 Antibody Selection and Maturation In vitro

15.5 Linking Antibodies to mRNA: Ribosome and mRNA Display

15.6 Advantages of Ribosome Display

15.7 Ribosome Display Systems

15.8 Antibody Generation by Ribosome Display

15.9 Summary

References

Chapter 16: Anti-Idiotypic Antibodies

16.1 Introduction

16.2 Basic Concepts

16.3 Physiological Role of Anti-idiotypic Antibodies

16.4 Anti-Idiotypic Antibody Responses

16.5 Anti-Idiotypic Antibodies in Cancer

16.6 Anti-idiotypic Antibodies in Other Diseases

16.7 Concluding Remarks

References

Chapter 17: Non-Antibody Scaffolds as Alternative Therapeutic Agents

17.1 Introduction

17.2 Motivation for Therapeutic Use of Alternative Binding Proteins

17.3 Single Domain Immunoglobulins

17.4 Scaffold Proteins Presenting a Contiguous Hypervariable Loop Region

17.5 Scaffold Proteins for Display of Individual Extended Loops

17.6 Scaffold Proteins Providing a Rigid Secondary Structure Interface

17.7 Non-Antibody Scaffolds Stepping into the Clinic

17.8 Conclusions and Outlook: Therapeutic Potential and Ongoing Developments

References

Chapter 18: Antibody-Directed Enzyme Prodrug Therapy (ADEPT)

18.1 Introduction and Basic Principles of ADEPT

18.2 Pre-clinical Studies

18.3 Clinical Studies

18.4 Immunogenicity

18.5 Important Considerations/Outlook

Acknowledgments

Abbreviations

References

Chapter 19: Engineered Antibody Domains as Candidate Therapeutics

19.1 Introduction

19.2 eAd Structure and Function

19.3 eAd Libraries

19.4 eAds against HIV-1

19.5 eAds Targeting Cancer

19.6 eAds against Inflammation

19.7 eAds against Hematological Disorders

19.8 Conclusions

Acknowledgments

References

Chapter 20: Chimeric Antigen Receptors – CARs

20.1 Introduction

20.2 Chimeric Antigen Receptors – CARs

20.3 Preclinical Studies

20.4 Therapeutic Considerations

20.5 Perspectives

20.6 Conclusions

References

Chapter 21: Emerging Alternative Production Systems

21.1 Introduction

21.2 Production Systems

21.3 Outlook

Abbreviations

References

Volume II: Clinical Development of Antibodies

Part IV: The Way into the Clinic

Chapter 22: Process Development and Manufacturing of Therapeutic Antibodies

22.1 Introduction

22.2 Upstream Processing

22.3 Downstream Processing

22.4 Formulation Development

22.5 Commercial Manufacturing Processes

22.6 Analytics

22.7 Overall Process Development Strategies and Outlook

Acknowledgments

References

Chapter 23: The Immunogenicity of Therapeutic Antibodies

23.1 Introduction

23.2 Immunogenicity and the Immune System

23.3 Factors Influencing Immunogenicity

23.4 Clinical Consequences of Immunogenicity of Abs

23.5 Bioanalytical Assessment of ADAs against Therapeutic Antibodies

23.6 Immunogenicity Prediction Tools

23.7 Reduction of Immunogenicity of Abs

23.8 A Look into the Future – The Rise of Antibody-Based Drugs

23.9 Conclusions

References

Chapter 24: Biosimilar Monoclonal Antibodies

24.1 Introduction

24.2 EU Approach to Biosimilars

24.3 US Biosimilars

24.4 Follow-On Monoclonal Antibodies in Emerging Markets

24.5 Technical Development and Analytical Characterization of Biosimilar Monoclonal Antibodies

24.6 Non-Clinical and Clinical Development of Biosimilar Monoclonal Antibodies/Pharmacovigilance and Risk Management

Acknowledgments

Abbreviations

References

Chapter 25: Patent Issues Relating to Therapeutic Antibodies

25.1 Why Patents Matter

25.2 Types of Patent Protection in the Field of Therapeutic Antibodies

25.3 Freedom to Operate

25.4 Protecting New Developments

25.5 Management of Own and Third-Party Patents

25.6 Patent Exploitation Options and Business Models

25.7 Outlook

25.8 Reference Materials and Further Reading

Part V: Therapeutic Antibody Pipeline

Chapter 26: Monoclonal Antibody Cancer Treatments in Phase III Clinical Trials

26.1 Introduction

26.2 Antibodies for Use in Lymphoma and Related Diseases

26.3 Anti-EpCAM Antibodies: A Lesson in History and What Remains

26.4 Antibodies Against Epithelial Growth Factor Targets

26.5 Insulin-Like Growth Factor Type I Receptor Antibodies

26.6 Antibodies for Use in Renal Cell Carcinoma

26.7 Antibodies for Use in Ovarian Cancer

26.8 Blockage of Immunological Checkpoints

26.9 Miscellaneous Diseases and Targets

26.10 Summary

References

Chapter 27: Antibodies in Cancer Treatment: Early Clinical Development

27.1 Introduction

27.2 Harnessing Innate Immunity

27.3 Alteration of Intracellular Signaling

27.4 Immunoconjugates

27.5 The Three U's: Mechanisms of Unique, Unclear, or Unknown Function

27.6 Summary

References

Chapter 28: Targeting Angiogenesis by Therapeutic Antibodies

28.1 Introduction

28.2 Therapeutic Antibodies

28.3 Conclusion

Abbreviations

References

Chapter 29: Antibodies in Phase III Studies for Immunological Disorders

29.1 Introduction

29.2 Antibody Targets in Phase III Trials

29.3 Summary

References

Chapter 30: Monoclonal Antibodies in Phase 1 and 2 Studies for Immunological Disorders

30.1 Introduction

30.2 General Overview of the Immune System and Key Pathways Driving Inflammatory Diseases

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

30.4 Mechanisms of Target Modulation Utilized by Monoclonal Antibodies

30.5 Optimizing mAbs for Efficacy and Safety

30.6 Summary

References

Chapter 31: MAbs Targeting Soluble Mediators in Phase 1 and 2 Clinical Studies Immunological Disorders

31.1 Introduction

References

Chapter 32: T Cell Inhibitors in Phase 1 and 2 Clinical Studies for Immunological Disorders

32.1 Introduction

32.2 T-Cell Inhibitors

32.3 Anti-T-Cell Costimulators

References

Chapter 33: B-Cell Inhibitors in Phase 1 and 2 Clinical Studies for Immunological Disorders

33.1 Introduction

33.2 Anti-CD19

33.3 Anti-BAFF (Blys)

33.4 Anti-CD20

References

Chapter 34: Inhibitors of Leukocyte Adhesion and Migration in Phase 1 and 2 Clinical Studies for Immunological Disorders

34.1 Introduction

34.2 Inhibitors of Leukocyte Adhesion and Migration

References

Chapter 35: Toll-Like Receptor Inhibitors in Phase 1 and 2 Clinical Studies for Immunological Disorders

35.1 Introduction

35.2 Toll-Like Receptor Inhibitors

References

Chapter 36: IgE Inhibitors in Phase 1 and 2 Clinical Studies for Immunological Disorders

36.1 Introduction

36.2 IgE Inhibitors

References

Chapter 37: Complement Inhibitors in Phase 1 and 2 Clinical Studies for Immunological Disorders

37.1 Introduction

37.2 Complement Inhibitors

References

Chapter 38: mAbs Targeting Apoptosis, Angiogenesis Inhibitors, and Other mAbs in Phase 1 and 2 Clinical Studies for Immunological Disorders

38.1 mAbs Targeting Apoptosis

38.2 Angiogenesis Inhibitors

38.3 Other mAbs

References

Chapter 39: In vitro Studies and Clinical Trials about Monoclonal Antibodies Used in Infectiology

39.1 Introduction and Infectious Context

39.2 Historical of Antibodies Used in Infectiology and Previous Clinical Trials

39.3 General Mechanisms of Action

39.4 Mode of Production of Anti-Infectious Antibodies

39.5 Anti-Infectious Monoclonal Antibodies Against Bacteria and Associated Toxins

39.6 Viral Diseases and Anti-Infectious Monoclonal Antibodies

39.7 Perspectives and Future Development of Antimycotic Monoclonal Antibodies

39.8 Conclusion

Acknowledgments

Author Contributions

Funding

Transparency Declarations Sections and Conflicts of Interest

References

Chapter 40: Immunotherapeutics for Neurological Disorders

40.1 Introduction

40.2 Alzheimer's Disease

40.3 Parkinson's Disease and Dementia with Lewy Bodies

40.4 Huntington's Disease

40.5 Amyotrophic Lateral Sclerosis

40.6 Transmissible Spongiform Encephalopathies

40.7 Conclusion

Acknowledgments

References

Part VI: Gaining Marketing Approval

Chapter 41: Regulatory Considerations in the Development of Monoclonal Antibodies for Diagnosis and Therapy*

41.1 Introduction

41.2 Regulatory Authority

41.3 Chemistry, Manufacturing, and Controls Considerations

41.4 Considerations for Nonclinical Testing

41.5 Immunogenicity

41.6 Conclusions

Acknowledgments

References

Chapter 42: Regulatory Review: Clinical to Market Transition

42.1 Introduction

42.2 General Considerations for the Clinical Development of mAbs

42.3 The Need for Regulatory Validation of the Development Program

42.4 The Approach of Agencies for Clinical Review of mAb

42.5 Strategic Regulatory Options for Rapid Market Access

42.6 Pivotal Clinical Trials for mAb

42.7 Specific Considerations for Early Development Clinic Studies of mAb

References

Chapter 43: Monoclonal Antibody Nomenclature for Clinical Studies (USA)1

43.1 Elements of a Name

43.2 Sequence of Stems and Infixes

43.3 Target/Disease Class Infix

43.4 USAN Modified Designations for Monoclonal Antibodies

43.5 Required Application Information

Volume III: Approved Therapeutic Antibodies

Part VII: Approved Therapeutic Antibodies

Chapter 44: Oligoclonal and Polyclonal Antibody Preparations

44.1 Introduction

44.2 Oligoclonal Antibodies

44.3 General Questions/Concerns

44.4 Uses/Applications of Oligoclonal Antibodies

44.5 Infectious Disease

44.6 FDA/Regulatory Considerations

44.7 Polyclonal Antibodies

44.8 Production of Polyclonal Antibodies

44.9 Immunogen Properties and Preparations

44.10 Carrier Proteins for Immunogen Preparation

44.11 Choice of Animal

44.12 Adjuvants

44.13 Route of Injection

44.14 Collecting and Processing of Blood

44.15 Antibody Purification

44.16 Polyclonal Antibody Derives Therapeutics (Clinical Utility)

44.17 Recombinant Polyclonal Antibodies

44.18 Summary

References

Chapter 45: Adalimumab (Humira®)

45.1 Overview

45.2 Basic Principles of Clinical Use

45.3 Safety

45.4 Use in Approved Indications

45.5 Clinical Studies in Intestinal Behçet Disease

45.6 Clinical Studies in Uveitis

45.7 Clinical Studies in Hidradenitis Suppurativa

45.8 Early-Stage Clinical Studies in Sarcoidosis

References

Chapter 46: Alemtuzumab (Lemtrada, MabCampath)1

46.1 Overview

46.2 Basic Principles

46.3 Antibody Features and Production

46.4 Molecular Target and Target Expression

46.5 Mechanism of Cell Lysis

46.6 Immunogenicity and Antiglobulin Response

46.7 Pharmacokinetic Studies

46.8 Clinical Studies in Chronic Lymphocytic Leukemia (CLL)

46.9 Clinical Studies in Multiple Sclerosis

46.10 Clinical Studies in Other Indications

References

Chapter 47: Basiliximab (Simulect®) and Daclizumab (Zenapax®)

47.1 Background

47.2 Clinical Use in Human Organ Transplantation

47.3 Clinical Use of IL-2R Antibodies in Non-organ Transplant Conditions

47.4 Conclusion

References

Chapter 48: Belimumab (Benlysta®)

48.1 Introduction

48.2 Basic Principles

48.3 Clinical Aspects of Belimumab Therapy

48.4 Summary

List of abbreviations

References

Chapter 49: Brentuximab Vedotin (Adcetris®) for the Treatment of CD30-Positive Hematologic Malignancies

49.1 Introduction

49.2 CD30

49.3 Preclinical Activity of Brentuximab Vedotin

49.4 Clinical Development of Brentuximab Vedotin

49.5 Future Perspectives

Acknowledgments

References

Chapter 50: Canakinumab (ILARIS®)

50.1 Introduction

50.2 Production, Pharmacology, and Pharmacokinetics of Canakinumab

50.3 Clinical Trials

50.4 Outlook and Summary

References

Chapter 51: Catumaxomab (Removab) – Trifunctional Antibodies: Combining Direct Tumor Cell Killing with Therapeutic Vaccination

51.1 Introduction

51.2 Manufacturing of trAbs

51.3 The Mode of Action of trAbs in Tumor Treatment

51.4 From Bench to Bedside with the Triomab® trAb Family

51.5 Potential Biomarkers Along trAb Treatment Concept

51.6 Concluding Remarks

Acknowledgments

References

Chapter 52: Cetuximab (Erbitux)

52.1 Nature, Role in Disease, Biology of the Target

52.2 Origin and Development of Erbitux

52.3 Mechanism of Action

52.4 Preclinical and Clinical Results

52.5 Production

52.6 Cetuximab in Clinics

52.7 Outlook

References

Websites

Chapter 53: Denosumab (Prolia®)

53.1 Introduction

53.2 Clinical Studies

53.3 Guidelines of the FDA (Website of FDA) for Denosumab (Prolia)

53.4 Summary and Outlook

References

Websites

Chapter 54: Efalizumab (Raptiva)

54.1 Introduction

54.2 Development and Characterization of the Antibody

54.3 Efalizumab in the Treatment of Psoriasis

54.4 Pharmacology and Toxicology of Efalizumab

54.5 Clinical Development of Efalizumab

54.6 Health-Related Quality of Life (HRQoL)

54.7 Safety and Tolerability

54.8 Efalizumab: Reassessment of Benefit–Risk Ratio and Suspension of Marketing Authorization

References

Chapter 55: Calicheamicin Conjugates: Gemtuzumab Ozogamicin (Mylotarg), Inotuzumab Ozogamicin

55.1 Introduction

55.2 Target Antigen Selection in Therapy with ADC

55.3 Conjugate Design/Preclinical Activity

55.4 Mechanisms of Action

55.5 Potential Mechanisms of Resistance

55.6 Clinical Trials

55.7 Summary and Conclusions

References

Chapter 56: Golimumab (Simponi®)

56.1 Introduction

56.2 Characterization and Preclinical Evaluation

56.3 First-in-Humans Study

56.4 Pivotal Clinical Studies

56.5 Market Competitors

References

Chapter 57: Yttrium-90 Ibritumomab Tiuxetan (Zevalin®)

57.1 Introduction

57.2 Basic Principles of Radioimmunotherapy

57.3 Development and Advantages of ⁹⁰Y-Ibritumomab Tiuxetan

57.4 Preclinical and Clinical Results

57.5 Outlook

References

Chapter 58: Infliximab (Remicade®)

58.1 Antibody Characteristics

58.2 Preclinical Characterization

58.3 Pharmacokinetics

58.4 Clinical Response

58.5 Safety

58.6 Summary

References

Chapter 59: Ipilimumab (Yervoy®)

59.1 Introduction

59.2 Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4)

59.3 Ipilimumab, Mechanism of Action

59.4 Pharmacokinetics

59.5 Melanoma

59.6 Prostate Cancer

59.7 Lung Cancer

59.8 Patterns of Response with Ipilimumab (Immune-Related Response Criteria)

59.9 Adverse Events

59.10 Conclusions

References

Chapter 60: Muromonab-CD3 (Orthoclone OKT®3)

60.1 Introduction

60.2 Production of mAbs

60.3 Pharmacology of Muromonab-CD3

60.4 Therapeutic Use

60.5 Cytokine Release Syndrome

60.6 Consequences of Immunosuppression

60.7 Withdrawal from the Market

References

Chapter 61: Nimotuzumab: A Humanized Anti-EGFR Antibody

61.1 Overview

61.2 Head and Neck

61.3 Glioma

61.4 Pediatric Glioma

61.5 Esophageal and Gastric Cancer

61.6 Pancreatic Cancer

61.7 Non-Small Cell Lung Cancer (NSCLC)

61.8 Concluding Remarks

References

Chapter 62: Obinutuzumab (Gazyva®), a Novel Glycoengineered Type II CD20 Antibody for the Treatment of Chronic Lymphocytic Leukemia and Non-Hodgkin's Lymphoma

62.1 In vitro Mechanism of Action of Type I and Type II CD20 Antibodies

62.2 Generation of Obinutuzumab

62.3 Obinutuzumab is a Classical Type II CD20 Antibody

62.4 The Epitope Recognized by Obinutuzumab

62.5 CDC Activity of Obinutuzumab

62.6 Direct Cell Death Induction by Obinutuzumab

62.7 Glycoengineering of Obinutuzumab

62.8 In vitro NK Cell and Neutrophil ADCC and Macrophage ADCP Activity of Obinutuzumab

62.9 Ex vivo Whole Blood B-Cell Depletion by Obinutuzumab

62.10 In vivo Activity of Obinutuzumab in Xenograft Models

62.11 In vivo Activity of Obinutuzumab in Combination with Chemotherapy, Bcl-2, and MDM2 Inhibitors

62.12 B-Cell Depletion by Obinutuzumab in Cynomolgus Monkeys

62.13 Conclusion from Nonclinical Pharmacology Studies with Obinutuzumab

62.14 Clinical Experiences with Obinutuzumab

62.15 Early Clinical Experience with Obinutuzumab in B-Cell Lymphoma

62.16 Phase Ib and II Experience with Obinutuzumab in B-Cell Lymphoma

62.17 Phase III Studies with Obinutuzumab in B-Cell Lymphoma

62.18 Obinutuzumab in CLL: Early Experience and Ongoing Phase II Studies

62.19 Phase III Experience with Obinutuzumab: The CLL11 Trial

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

63.1 Introduction and Preliminary Comments

63.2 Physical and Immunochemical Characteristics of OFA Compared to RTX

63.3 Functional Characterizations

63.4 CD20: It Is certainly a Good Target, but How Well Characterized Is It?

63.5 Key Results of Clinical Trials with OFA

63.6 Summary and Future Directions

Abbreviations

63.7 Disclosures

References

Chapter 64: Omalizumab (Xolair) – Anti-Immunoglobulin E Treatment in Allergic Diseases

64.1 Introduction

64.2 The Biology of the IgE Molecule

64.3 IgE Receptors

64.4 Cell Distribution of IgE

64.5 Physiologic and Pathophysiologic Significance of IgE

64.6 The Concept of Anti-IgE-Based Treatment

64.7 Construction of the Monoclonal Anti-IgE Molecule

64.8 Efficacy

64.9 Anti-Inflammatory Effects of Omalizumab

64.10 Pharmacological Properties of Omalizumab

64.11 Adverse Effects

64.12 Indications

64.13 Contraindications

64.14 Preparation for Use

64.15 Administration

64.16 Dosing of Omalizumab

64.17 Response to Treatment

64.18 Assessment of Therapeutic Response

64.19 Monitoring of Therapy

64.20 Drug Interactions

64.21 Pregnancy and Lactation

64.22 Cost

64.23 Non-approved Diseases

64.24 Conclusions

Acknowledgments

References

Websites

Chapter 65: Palivizumab (Synagis®)

65.1 Nature, Role in Disease, and Biology of the Target

65.2 Origin, Engineering, and Humanization of the Antibody

65.3 Mechanism of Action and Preclinical Results

65.4 Production, Downstream Processing, and Galenics of the Antibody

65.5 Summary of Results from Clinical Studies

65.6 Indications and Usage

65.7 Clinical Reports after Approval

65.8 Protective Efficacy as a Function of Palivizumab Serum Concentration?

65.9 Postmarketing Experience with Regard to Adverse Events (AEs)

65.10 Toward Improved Versions of Palivizumab

65.11 Summary

Acknowledgments

Abbreviations

References

Chapter 66: Panitumumab (Vectibix®): A Treatment for Metastatic Colorectal Cancer

66.1 Introduction

66.2 Panitumumab (Vectibix)

66.3 Results from Clinical Studies

66.4 Summary and Outlook

References

Chapter 67: Pertuzumab (Perjeta®)

67.1 HER2-Positive Breast Cancer

67.2 Mechanisms of Trastuzumab Resistance

67.3 Preclinical Development

67.4 Pertuzumab Clinical Development

67.5 Pertuzumab Cardiac Safety Profile

References

Chapter 68: Ranibizumab (Lucentis): a New Anti-Angiogenic Treatment in Ophthalmology

68.1 Introduction

68.2 Ranibizumab: Clinical Studies in Retinal Disorders

68.3 Other Molecules with Anti-VEGF Effect of Clinical Use in Retinal Disorders

References

Chapter 69: Raxibacumab, Human Monoclonal Antibody against Anthrax Toxin

69.1 Introduction

69.2 Development of Raxibacumab

69.3 Demonstration of Effectiveness under the Animal Rule

69.4 Safety

69.5 Dosing

69.6 Indication

69.7 Conclusion

Abbreviations

References

Chapter 70: Rituximab (Rituxan®)

70.1 Introduction

70.2 Rituximab Clinical Data in B-Cell Lymphoma

70.3 Rituximab in Autoimmune Disorders

70.4 Development of a Subcutaneous Rituximab Formulation (Rituximab SC) in B-Cell Lymphoma and CLL

70.5 Summary and Conclusions

References

Websites

Chapter 71: Tocilizumab (Actemra®)

71.1 Introduction

71.2 Biological Activities and Signaling of IL-6

71.3 Targeting IL-6 with Monoclonal Antibodies

71.4 Targeting IL-6 in Rheumatoid Arthritis

71.5 Targeting IL-6 in Systemic-Onset Juvenile Idiopathic Arthritis

71.6 Targeting IL-6 in Castleman's Disease

71.7 Other Indications

71.8 Adverse Events Associated with Targeting the IL-6 Receptor

71.9 Current State of Play

References

Chapter 72: Trastuzumab (Herceptin®) and Ado-Trastuzumab Emtansine (Kadcyla®): Treatments for HER2-Positive Breast Cancer

72.1 Introduction

72.2 Metastatic Breast Cancer

72.3 Early Breast Cancer

72.4 Cardiac Adverse Events

72.5 Infusion-Related Reactions

72.6 Age Considerations

72.7 Patient Considerations

72.8 Dosing/Scheduling

72.9 Ado-Trastuzumab Emtansine (T-DM1), Trade Name Kadcyla

72.10 Safety and Side Effects

72.11 FDA Approval

72.12 Conclusions

References

Chapter 73: Ustekinumab (Stelara®)

73.1 Introduction

73.2 Psoriasis

73.3 Psoriatic Arthritis

73.4 Crohn's Disease

73.5 Multiple Sclerosis

73.6 Meta Analyses on Long-Term Use

73.7 Ongoing Studies, New Indications, and Outlook

References

Chapter 74: Abciximab (Reopro®), Bevacizumab (Avastin®), Certolizumab Pegol (Cimzia®), Eculizumab (Soliris®), Natalizumab (Tysabri®)

74.1 Abciximab (Reopro)

74.2 Bevacizumab (Avastin)

74.3 Certolizumab Pegol (Cimzia)

74.4 Eculizumab (Soliris)

74.5 Natalizumab (Tysabri)

References

Chapter 75: Itolizumab (Alzumab®), Mogamulizumab (Poteligeo®), and Tositumomab (Bexxar®)

75.1 Itolizumab (Alzumab)

75.2 Mogamulizumab (Poteligeo)

75.3 Tositumomab; Iodine ¹³¹I Tositumomab (Bexxar)

References

Further Reading

Information Sources

Part VIII: In vivo Diagnostics

Chapter 76: Radiolabeled Antibodies for Diagnostic Imaging

76.1 Introduction

76.2 Oncology

76.3 Cardiology

76.4 Infection

76.5 Summary

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

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Edited by Stefan Dübel and Janice M. Reichert

Handbook of Therapeutic Antibodies

Volume I: Defining the Right Antibody Composition

Second Edition

Wiley Logo

Edited by Stefan Dübel and Janice M. Reichert

Handbook of Therapeutic Antibodies

Volume II: Clinical Development of Antibodies

Second Edition

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Edited by Stefan Dübel and Janice M. Reichert

Handbook of Therapeutic Antibodies

Volume III: Approved Therapeutic Antibodies

Second Edition

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Edited by Stefan Dübel and Janice M. Reichert

Handbook of Therapeutic Antibodies

Volume IV: Approved Therapeutic Antibodies and in vivo Diagnostics

Second Edition

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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.

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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>.

© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

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

Quick Reference List of Antibodies by Brand Name

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.

A substantial part of this second edition of the Handbook is devoted to emerging developments of all aspects of this process, including progress toward novel ideas for alternative therapeutic paradigms that might make the IgG obsolete.

Finally, approved antibody therapeutics are presented in detail in separate chapters, allowing the clinicians to quickly gain a comprehensive understanding of individual therapeutics.

In such a fast-developing area, it is difficult to keep pace with the rapidly growing information.

For example, a PubMed search of the term Herceptin in 2013 yields nearly 6000 articles, an ∼4x increase over the 1500 citations at time of the first edition in Dec. 2006. Consequently, our goal was to extract the essentials from this vast resource, with the aim of offering a comprehensive basis of knowledge on all relevant aspects of antibody therapeutics for the researcher, the company expert, and the bedside clinician.

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

Foreword to the First Edition

The most characterized class of proteins are the antibodies. After more than a century of intense analysis, antibodies continue to amaze and inspire. This Handbook of Therapeutic Antibodies is not just an assembly of articles but rather a state-of-the-art comprehensive compendium, which will appeal to all those interested in antibodies, whether from academia, industry, or the clinic. It is an unrivaled resource which shows how mature the antibody field has become and how precisely the antibody molecule can be manipulated and utilized.

From humble beginnings when the classic monoclonal antibody paper by Kohler and Milstein ended with the line, such cultures could be valuable for medical and industrial use to the current Handbook you hold in your hand, the field is still in its relative infancy. As information obtained from clinical studies becomes better understood then further applications will become more streamlined and predictable. This Handbook will go a long way to achieving that goal. With the application of reproducible recombinant DNA methods the antibody molecule has become as plastic and varied as provided by nature. This then takes the focus away from the antibody, which can be easily manipulated, to what the antibody recognizes. Since any type, style, shape, affinity, and form of antibody can be generated, then what the antibody recognizes now becomes important.

All antibodies have one focus, namely, its antigen or more precisely, its epitope. In the realm of antibody applications antigen means target. The generation of any sort of antibody and/or fragment is now a relatively simple procedure so the focus of this work has shifted to the target, and rightly so. Once a target has been identified then any type of antibody can be generated to that molecule. Many of the currently US Food and Drug Administration (FDA)-approved antibodies were obtained in this manner. If the target is unknown, then the focus is on the specificity of the antibody and ultimately the antigen it recognizes.

As the field continues to mature, the applications of antibodies will essentially mimic as much of the natural human immune response as possible. In this respect, immunotherapy may become immunomanipulation, where the immune system is being manipulated by antibodies. With the success of antibody monotherapy the next phase of clinical applications is the use of antibodies with standard chemotherapy, and preliminary studies suggest the combination of these two modalities is showing a benefit to the patient. When enough antibodies become available then cocktails of antibodies will be formulated for medical use. Since the natural antibody response is an oligoclonal response then cocktails of antibodies can be created by use of various in vitro methods to duplicate this in a therapeutic setting. In essence, this will be oligotherapy with a few antibodies. After all, this is what nature does and duplicating this natural immune response may be effective immunotherapy.

And all of this brings us back full circle to where it all starts and ends, the antibody molecule. No matter what version, isotype, form, or combination used the antibody molecule must first be made and shown to be biologically active. Currently, many of the steps and procedures to generate antibodies can be obtained in kit form and therefore are highly reproducible, making the creation of antibodies a straightforward process. Once the antibody molecule has been generated it must be produced in large scale for clinical and industrial applications. More often than not this means inserting the antibody genes into an expression system compatible with the end use of the antibody (or fragment). Since many of the steps in generating clinically useful antibodies are labor intensive and costly, care must be used to select antibodies with the specificity and activity of interest before they are mass produced. For commercial applications the FDA will be involved so their guidelines must be followed.

Stating the obvious, it would have been nice to have this Handbook series in the late 1970s when I entered the antibody field. It certainly would have made the work a lot easier! And here it is, about 30 years later, and the generation of antibodies has become handbook easy. In this respect I am envious of those starting out in this field. The recipes are now readily available so the real challenge now is not in making antibodies but rather in the applications of antibodies. It is hoped that this Handbook will provide a bright beacon where others may easily follow and generate antibodies which will improve our health. The immune system works and works well; those using this Handbook will continue to amaze and inspire.

December 2006

Mark Glassy

The Rajko Medenica Research Foundation,

San Diego, CA, USA

Shantha West, Inc., San Diego, CA, USA

Foreword to the Second Edition

This latest edition of the Handbook of Therapeutic Antibodies represents a milestone in the field. With over 75 contributions on all phases of antibody science, the reader has ample proof that antibodies do indeed continue to amaze and inspire. And yet, the antibody field can still be considered to be in its early stage of growth, or rather, more like adolescence.

Our understanding of antibodies is now at the point that the key technical and ethical limitations have been solved and understood. This was the field's infancy. Now, in adolescence, it is time for the real work of antibodies to mature. This means it is at the stage when they should demonstrate their real power to immunoregulate health and disease. So far, just a handful of antibodies have been approved for human use and these are well described in this Handbook. Although some antibodies may be limited in scope, this is just the beginning as the field matures. As discussed in the first Forward to this Handbook, the natural human immune response is an oligoclonal response. More importantly, and stating the obvious, this oligoclonal immune response works. This then challenges those in the field to develop an understanding of how to pragmatically use this approach in immunoregulating disease. What few antibodies can be combined in effective ways to mimic the natural human immune response? What mAb cocktails can be used as treatment modalities? That is the path ahead of us.

The antibodies currently being used in the clinic have helped to pave the way for the next wave of products. To paraphrase, these current products are standing on the shoulders of those preceding them. And those yet to come will learn from the past and better serve for human health.

It has been 7 years since the first edition and the antibody field has significantly grown during this time. This current Handbook still continues to shine brightly and its beacon still lights a broad path for those who are interested in the antibody field. The lessons learned from human immunology are well described here and show that the future of therapeutic antibodies will soon be in its Golden Age.

September 2013

Mark Glassy

The Integrated Medical Sciences Association Foundation,

San Diego, CA, USA

Nascent Biologics, Inc., San Diego, CA, USA

List of Contributors

Nasimul Ahsan

College of Medicine-University of Florida

North Florida South Georgia VA Health System

S W Archer Road

Gainesville, FL 32608

USA

James Allen

Institute of Structural and Molecular Biology

University College London

Darwin Building

Gower Street

London WC1E 6BT

UK

Ignacio Anegon

INSERM Unit 1064

Transgenic Rats Nantes Platform

ITUN CHU de Nantes

Nantes F44093

France

Fernando Moreno Anton

Hospital Clínico San Carlos

Department of Medical Oncology

Calle Profesor Martín Lagos S/N

Madrid 28040

Spain

Christian Antoni

Sanofi

VP, head development franchise immunology and inflammation

Corporate Drive

Bridgewater, NJ 08807

USA

Rosalin Arends

MedImmune LLC, Sir Aaron Klug Building

Granta Park

Cambridge CB21 6GH

UK

Michaela A.E. Arndt

National Center for Tumor Diseases and German Cancer Research Center

Department of Translational Immunology

Im Neuenheimer Feld 460

D-69120 Heidelberg

Germany

Suzanne Avis

Recombinant Antibody Technology Ltd.

Babraham Research Campus

Babraham

Cambridge CB22 3AT

UK

Marina Bacac

Roche Pharmaceutical Research and Early Development

Oncology Discovery & Translational Area

Roche Innovation Center Zurich

Wagistrasse 18

CH-8952 Schlieren

Switzerland

Kenneth D. Bagshawe

Imperial College London

Department of Oncology

Charing Cross Campus

Fulham Palace Road

London W6 8RF

UK

Joost Bakker

Genmab

Yalelaan 60

CM Utrecht

The Netherlands

and

Scicomvisuals

Duivendrechtsekade 85-A

AJ Amsterdam

The Netherlands

Harald Becker

Wetzbach 26D

Zwingenberg

Germany

Mark Bodmer

UCB New Medicines

Bath Road

Slough SL1 3WE

UK

Axel Böhnke

Grenzacherstrasse 124

Basel

Switzerland

Sally D. Bolmer

Emerson Avenue

Palo Alto CA 94301

USA

Louis Bont

Dept of Pediatrics & Dept of Immunology

Room KE4.133.1

Lundlaan 6

EA Utrecht

The Netherlands

and

University Medical Center Utrecht

DeptPediatric Immunology and Infectious Diseases

Lundlaan 6

AB Utrecht

The Netherlands

Hossein Borghaei

Temple Fox Chase Cancer Center

Department of Medical Oncology

Cottman Avenue

Philadelphia

PA

Michael Braunagel

SDir Strategic Alliances and Licensing

Actigen Limited

St John's Innovation Centre

Cowley Road

Cambridge CB4 0WS

UK

Frank R. Brennan

UCB Pharma

New Medicines

Non-Clinical Development

Bath Road

Slough

SL13WE

UK

Carsten Brockmeyer

Formycon AG

Fraunhoferstr 15

Martinsried

Germany

Marianne Brüggemann

Recombinant Antibody Technology Ltd.

Babraham Research Campus

Babraham

Cambridge CB22 3AT

UK

Roland Buelow

Recombinant Antibody Technology Ltd.

Babraham Research Campus

Babraham

Cambridge CB22 3AT

UK

and

Open Monoclonal Technology, Inc.

Ross Road

Suite A

Palo Alto CA 94303

USA

Raymund Buhmann

University of Munich-Grosshadern

Department of Medicine III

Munich

Germany

Oscar Roberto Burrone

International Centre for Genetic Engineering and Biotechnology

Padriciano 99

Trieste

Italy

Björn Chapuy

Dana-Faber Cancer Institute, Medicine

Mayer 513

Binney ST

MA 02115

Boston

Ravi V. J. Chari

ImmunoGen, Inc.

Winter Street

Waltham

Massachusetts 02451

USA

Weizao Chen

National Institutes of Health

Protein Interactions Group

Cancer and Inflammation Program

Center for Cancer Research

National Cancer Institute

Frederick

Maryland 21702

USA

Kerry A. Chester

UCL Cancer Institute

Antibody Based Medicines

Department of Oncology

Huntley Street

London WC1E 6BT

UK

Ruhe Chowdhury

Richard Dimbleby

Laboratory of Cancer Research

New Hunt House

Pilgrimage St

London SE1 1UL

UK

Oya Cingoz

Columbia University

College of Physicians and Surgeons

Department of Biochemistry and Molecular Biophysics

West 168th Street

New York

NY

USA

Edward Coulstock

Biopharm Innovation

GlaxoSmithKline

Unit 315 Cambridge Science Park

Cambridge

CB4 0WG

UK

David P. D'Cruz

Louise Coote Lupus Unit

St Thomas' Hospital

Westminster Bridge Road

SE1 7EH London

UK

Gabriele Dallmann

Biopharma Excellence GbR

% MTZ

Agnes-Pockels-Bogen 1

Munich

Germany

Peter Markus Deckert

Städtisches Klinikum Brandenburg

Abteilung Onkologie und Palliativmedizin

Hochstr 29

Brandenburg/Havel

Germany

Stefanie Derer

Christian-Albrechts-University Kiel

Division of Stem Cell Transplantation and Immunotherapy

Department of Medicine

Schittenhelmstr 12

Kiel

Germany

Guillaume Desoubeaux

Hôpital Bretonneau

CHU de Tours, Service de Parasitologie-Mycologie-Médecine tropicale

boulevard Tonnellé

CHU de TOURS Cedex

France

and

Université François Rabelais

CEPR – INSERM UMR U1100/EA 6305

10ter boulevard Tonnellé

Faculté de Médecine de TOURS

Cedex

France

Eugen Dhimolea

VU University Medical Center

Department of Hematology

De Boelelaan 1117

1081HV

Amsterdam

Eduardo Díaz-Rubio

Hospital Clínico San Carlos

Medical Oncology Department

C/Profesor Martín Lagos S/N

Madrid 28040

Spain

Dimiter S. Dimitrov

National Institutes of Health

Protein Interactions Group

Cancer and Inflammation Program

Center for Cancer Research

National Cancer Institute

Frederick

Maryland 21702

USA

Changhai Ding

University of Tasmania

Menzies Research Institute Tasmania

Private bag 23

Hobart

Tasmania 7000

Australia

Niels W.C.J. van de Donk

University Medical Center Utrecht

Department of Hematology Heidelberglaan 100

3584CX Utrecht

The Netherlands

and

VU University Medical Center

Department of Hematology

De Boelelaan 1117

1081HV Amsterdam

Stefan Dübel

Technische Universität Braunschweig

Institute of Biochemistry

Biotechnology

and Bioinformatics

Spielmannstr 7

Braunschweig

Germany

Christian Eckermann

Boehringer Ingelheim Pharma GmbH & Co. KG

Birkendorfer Street 65

Biberach a. d. Riss

Germany

Thomas Efferth

Johannes Gutenberg University

Department of Pharmaceutical Biology

Institute of Pharmacy and Biochemistry

Staudinger Weg 5

Mainz

Germany

Paul Ellis

Guys and St Thomas' NHS Trust

Guys Hospital

Great Maze Pond

London, SE1 9RT

UK

Thomas Elter

Universitätsklinik zu Köln

Centrum für Integrierte Onkologie Köln/Bonn (CIO)

Medizinisches Versorgungszentrum der Universität zu Köln

Deutsche CLL Studiengruppe

Facharzt für Innere Medizin

Hämatologie und Onkologie

Klinik I für Innere Medizin der

Germany

Barbara Enenkel

Boehringer Ingelheim Pharma GmbH & Co. KG

Birkendorfer Street 65

Biberach a. d. Riss

Germany

Carrie Enever

Biopharm Innovation

GlaxoSmithKline

Unit 315 Cambridge Science Park

Cambridge CB4 0WG

UK

Markus Fiedler

BioNTech AG

An der Goldgrube 12

Mainz

Germany

Martin Foerster

University Clinic Jena

Department of Pneumology & Allergy/Immunology Medical Clinic I

Germany

Andre Frenzel

Technical University of Braunschweig

Institute of Biochemistry and Biotechnology

Spielmannstr 7

Braunschweig

Germany

Jose Angel García-Sáenz

Hospital Clínico San Carlos

Department of Medical Oncology

Calle Profesor Martín Lagos S/N

Madrid 28040

Spain

Patrick Garidel

Boehringer Ingelheim Pharma GmbH & Co. KG

Birkendorfer Street 65

Biberach a. d. Riss

Germany

Mark C. Glassy

Nascent Biologics, Inc.

San Diego CA

USA

and

Integrated Medical Sciences Association Foundation

San Diego CA

USA

and

The Rajko Medenica Research Foundation

San Diego CA

USA

and

Shantha West, Inc.

San Diego CA

USA

Teresa Alonso Gordoa

Hospital Clínico San Carlos

Medical Oncology Department

C/Profesor Mart{í}n Lagos S/N

Madrid 28040

Spain

Hermann Gram

Forum 1

Novartis Institutes of BioMedical Research

CH-4002 Basel

Switzerland

Martin Gramatzki

Christian-Albrechts-University of Kiel

Division of Stem Cell Transplantation and Immunotherapy

Second Medical Department

Schittenhelmstr 12

Kiel

Germany

Larry Green

MedImmune LLC

Sir Aaron Klug Building

Granta Park

Cambridge CB21 6GH

UK

Rishab K. Gupta

Nascent Biologics, Inc.

San Diego

USA

and

David Geffen School of Medicine at UCLA

Department of Surgery

San Diego

USA

Bruce Hamilton

Biopharm Innovation

GlaxoSmithKline

Unit 315 Cambridge Science Park

Cambridge CB4 0WG

UK

Michael Hallek

University of Cologne

Department of Hematology and Oncology

Kerpener Street 62

50937, Köln

Germany

Mingyue He

Technology Research Group

The Babraham Institute Cambridge CB32 3AT

UK

Juergen Hess

TRION Pharma GmbH

Frankfurter Ring 193a

Munich

Germany

Karin Hohloch

Dep of Hematology and Medical Oncology

Göttingen Comprehensive Cancer Center

Georg-August-University

37099 Göttingen

Germany

Michael Hust

Technische Universität Braunschweig, Abteilung Biotechnologie

Institut für Biochemie

Biotechnologie und Bioinformatik

Spielmannstr 7

Braunschweig

Germany

Alexander Jacobi

Boehringer Ingelheim Pharma GmbH & Co. KG

Birkendorfer Street 65

Biberach a. d. Riss

Germany

Michael Jäger

TRION Research GmbH

Am Klopferspitz 19

Martinsried

Germany

Roy Jefferis

School of Immunity and Infection

College of Medical and Dental Sciences

University of Birmingham

Edgbaston

Birmingham

West Midlands B15 2TT

UK

Graeme Jones

University of Tasmania

Menzies Research Institute Tasmania

Private bag 23

Hobart

Tasmania 7000

Australia

Natasha Jordan

Louise Coote Lupus Unit

St Thomas' Hospital

Westminster Bridge Road

SE1 7EH London

UK

Thomas Jostock

Novartis Pharma AG

CH-4002

Basel

Switzerland

Onat Kadioglu

Johannes Gutenberg University

Department of Pharmaceutical Biology

Institute of Pharmacy and Biochemistry

Staudinger Weg 5

Mainz

Germany

Hitto Kaufmann

Boehringer Ingelheim Pharma GmbH & Co. KG

Birkendorfer Street 65

Biberach a. d. Riss

Germany

Christian Kellner

Christian-Albrechts-University Kiel

Division of Stem Cell Transplantation and Immunotherapy

Department of Medicine

Schittenhelmstr 12

Kiel

Germany

Stefan Kiesgen

National Center for Tumor Diseases

Heidelberg University Hospital

Department of Medical Oncology

Neuenheimer Feld 460

D-69120 Heidelberg

Germany

Scott Klakamp

MedImmune LLC

Sir Aaron Klug Building

Granta Park

Cambridge CB21 6GH

UK

Christian Klein

Roche Pharmaceutical Research and Early Development

Oncology Discovery & Translational Area

Roche Innovation Center Zurich

Wagistrasse 18

CH-8952 Schlieren

Switzerland

Daniel Klunker

TRION Pharma GmbH

Frankfurter Ring 193a

Munich

Germany

Mathias Knappenberger

Boehringer Ingelheim Pharma GmbH & Co. KG

Birkendorfer Street 65

Biberach a. d. Riss

Germany

Roland E. Kontermann

Universität Stuttgart

Institut für Zellbiologie und Immunologie

Allmandring 31

Stuttgart

Germany

Jürgen Krauss

National Center for Tumor Diseases

Heidelberg University Hospital

Department of Medical Oncology

Neuenheimer Feld 460

D-69120 Heidelberg

Germany

Claus Kroegel

University Clinic Jena

Department of Pneumology & Allergy/Immunology Medical Clinic I

Germany

Jonas Kügler

Technische Universität Braunschweig

Abteilung Biotechnologie

Institut für Biochemie

Biotechnologie und Bioinformatik

Spielmannstr.7

38106 Braunschweig

Germany

and

mAb-factory GmbH

Gelsenkirchenstr 5

Braunschweig

Germany

John M. Lambert

ImmunoGen Inc.

Winter Street

Waltham

Massachusetts 02451

USA

Holger Laux

Novartis Pharma AG

CH-4002

Basel

Switzerland

Marie-Paule Lefranc

Université Montpellier 2

Institut Universitaire de France

France

and

Laboratoire d'ImmunoGénétique Moléculaire

LIGM, Institut de Génétique Humaine IGH

UPR CNRS 1142, IMGT®

The International ImMunoGeneTics Information System®

Rue de la Cardonille

Montpellier Cedex 5

France

Cynthia A. Lemere

Harvard Medical School

Center for Neurologic Diseases

Brigham and Women's Hospital

Boston MA 02115

USA

Nicolas Leveziel

University Hospital of Poitiers

Department of Ophthalmology

Rue de la Miléterie

Poitiers 86021

France

Meina Liang

MedImmune LLC

Sir Aaron Klug Building

Granta Park

Cambridge CB21 6GH

UK

Horst Lindhofer

TRION Pharma GmbH

Frankfurter Ring 193a

Munich

Germany

and

TRION Research GmbH

Am Klopferspitz 19

Martinsried

Germany

Margaret A. Lindorfer

University of Virginia School of Medicine

Department of Biochemistry and Molecular Genetics

Jefferson Park Avenue

Charlottesville

VA 22908

USA

Stefan Lohse

Christian-Albrechts-University Kiel

Division of Stem Cell Transplantation and Immunotherapy, II.

Department of Medicine

Schittenhelmstr 12

Kiel

Germany

Alejandro López-Requena

Center of Molecular Immunology

Street and 15th Avenue

Atabey, Playa

Havana 11600

Cuba

Pamela M. K Lutalo

Louise Coote Lupus Unit

St Thomas' Hospital

Westminster Bridge Road

SE1 7EH London

UK

Biao Ma

Recombinant Antibody Technology Ltd.

Babraham Research Campus

Babraham

Cambridge CB22 3AT

UK

Nadim Mahmud

Brigham and Women's Hospital

Harvard Medical School

Department of Internal Medicine

Francis Street

Boston MA 02115

USA

Kevin Manley

University at Albany

Wadsworth Center

New York State Department of Health and

Department of Biological Sciences

Albany, NY 12208

USA

Andrew C.R. Martin

University College London

Institute of Structural and Molecular Biology

Darwin Building

Gower Street

London WC1E 6BT

UK

Athanasios Mavratzas

National Center for Tumor Diseases

Heidelberg University Hospital

Department of Medical Oncology

Im Neuenheimer Feld 460

D-69120 Heidelberg

Germany

Sohini Mazumdar

Clarion Healthcare

Financial Center

Boston MA 02111

USA

Anne Messer

University at Albany

Wadsworth Center

New York State Department of Health and Department of Biomedical Sciences

David Axelrod Institute

New Scotland Avenue

Albany, NY 12208

USA

Torsten Meyer

TU-Braunschweig

Institute of Biochemistry

Biotechnology and Bioinformatics

Spielmannstraße 7

Braunschweig

Germany

Thi-Sau Migone

GlaxoSmithKline

14200 Shady Grove Road

Rockville

MD 20850

USA

Gerhard Moldenhauer

Department of Translational Immunology

German Cancer Research Center and National Center for Tumor Diseases

Im Neuenheimer Feld 460

Heidelberg

Germany

Coralia Bueno Muiño

Hospital Infanta Cristina

Department of Medical Oncology

Parla, Madrid 28981

Spain

Dafne Müller

Universität Stuttgart

Institut für Zellbiologie und Immunologie

Allmandring 31

Stuttgart

Germany

Marc Ohresser

Université François-Rabelais de Tours

CNRS

GICC UMR 7292

Tours

France

Anthony J. Olszanski

Temple Fox Chase Cancer Center

Department of Medical Oncology

Cottman Avenue

Philadelphia

PA

Michael J. Osborn

Recombinant Antibody Technology Ltd.

Babraham Research Campus

Babraham

Cambridge CB22 3AT

UK

Deborah Owen

Patent Attorneys

Dehns

St Bride's House

Salisbury Square

London EC4Y 8JD

UK

Gilles Paintaud

Université François-Rabelais de Tours

CNRS

GICC UMR 7292

CHRU de Tours

Laboratory of Pharmacology-Toxicology

Tours

France

Christopher J. Palestro

Hofstra North Shore-LIJ School of Medicine

Hempstead

NY

USA

and

Division of Nuclear Medicine and Molecular Imaging

North Shore Long Island Jewish Health System

Manhasset

NY

USA

and

Division of Nuclear Medicine and Molecular Imaging

Long Island Jewish Medical Center

270-05 76th Avenue

New Hyde Park

NY 11040

USA

Paul W.H.I. Parren

Genmab

Yalelaan 60

CM Utrecht

The Netherlands

Matthias Peipp

Christian-Albrechts-University Kiel

Division of Stem Cell Transplantation and Immunotherapy

Department of Medicine

Schittenhelmstr 12

Kiel

Germany

Rolando Pérez

Center of Molecular Immunology

Street and 15th Avenue

Atabey, Playa

Havana 11600

Cuba

Ulf Petrausch

University Hospital Zürich

Klinik für Onkologie

Rämistrasse 100

Zurich

Switzerland

Susanne D. Pippig

Formycon AG

Fraunhoferstr 15

Martinsried

Germany

Ponraj Prabakaran

National Institutes of Health

Protein Interactions Group

Cancer and Inflammation Program

Center for Cancer Research

National Cancer Institute

Frederick

Maryland 21702

USA

and

Science Applications International Corporation-Frederick, Inc.

The Basic Research Program

Frederick

Maryland 21702

USA

Ingo Presser

Boehringer Ingelheim Pharma GmbH & Co. KG

Birkendorfer Street 65

Biberach a. d. Riss

Germany

Malgorzata Pupecka-Swider

Biopharm Innovation

GlaxoSmithKline

Unit 315 Cambridge Science Park

Cambridge CB4 0WG

UK

Tania Crombet Ramos

Center of Molecular Immunology

Clinical Research Direction

Ave 216, Esq 15. Atabey

Playa

Havana 11600

Cuba

Janice M. Reichert

Reichert Biotechnology Consulting LLC

Prospect Street

Framingham MA 01701

USA

M. Stacey Ricci

Food and Drug Administration

Division of Hematology and Oncology

Toxicology

Center for Drugs Evaluation and Research

New Hampshire Ave

HFD-107

Silver Spring

20993

USA

Barbara Rigby

Patent Attorneys

Dehns

St Bride's House

Salisbury Square

London EC4Y 8JD

UK

Lorin Roskos

MedImmune LLC

Sir Aaron Klug Building

Granta Park

Cambridge CB21 6GH

UK

Peter Ruf

TRION Research GmbH

Am Klopferspitz 19

Martinsried

Germany

José W. Saldanha

Division of Mathematical Biology

National Institute for Medical Research

The Ridgeway

Mill Hill

London NW7 1AA

UK

Melody Sauerborn

TNO Triskelion

Department of Bioanalysis

Utrechtseweg 48

HE Zeist

The Netherlands

Thomas Schirrmann

Technical University Braunschweig

Institute of Biochemistry and Biotechnology

Department of Biotechnology

Spielmannstr 7

Braunschweig

Germany

Karlheinz Schmitt-Rau

SR Healthcare Consulting

Mühlweg 2b

D-87459 Pfronten

Germany

Ean Jeong Seo

Johannes Gutenberg University

Department of Pharmaceutical Biology

Institute of Pharmacy and Biochemistry

Staudinger Weg 5

Mainz

Germany

Marjorie A. Shapiro

Food and Drug Administration

Division of Monoclonal Antibodies

Center for Drugs Evaluation and Research

Fishers Lane

HFD-123

Rockville MD 20872

USA

Surinder K. Sharma

UCL Cancer Institute

ADEPT and Translational Therapeutics

Department of Oncology

Huntley Street

London WC1E 6BT

UK

Stephanie C. Shubat

American Medical Association Director

United States Adopted Names Program (USAN)

AMA Plaza 330 N. Wabash Avenue

Chicago

Illinois 60611

USA

Rajeeva Singh

ImmunoGen, Inc.

Winter Street

Waltham

Massachusetts 02451

USA

Arne Skerra

Technische Universität München

Lehrstuhl für Biologische Chemie

Emil-Erlenmeyer-Forum 5

Freising-Weihenstephan

Germany

Benjamin Sommer

Novartis Pharma AG

CH-4002

Basel

Switzerland

Michael Stanglmaier

TRION Research GmbH

Am Klopferspitz 19

Martinsried

Germany

Patrick G. Swann

Food and Drug Administration

Division of Monoclonal Antibodies

Center for Drugs Evaluation and Research

Fishers Lane

HFD-123

Rockville MD 20872

USA

Burcin Taner

Mayo Clinic Florida

Department of Transplantation

San Pablo Road

Jacksonville FL 32224

USA

Michael J. Taussig

Technology Research Group

The Babraham Institute

Cambridge CB32 3AT

UK

Ronald P. Taylor

University of Virginia School of Medicine

Department of Biochemistry and Molecular Genetics

Jefferson Park Avenue

Charlottesville

VA 22908

USA

Lorenz Trümper

Dep of Hematology and Medical Oncology

Göttingen Comprehensive Cancer Center

Georg-August-University

37099 Göttingen

Germany

Florian Tomszak

Technische Universität Braunschweig

Abteilung Biotechnologie

Institut für Biochemie

Biotechnologie und Bioinformatik

Spielmannstr 7

Braunschweig 38106

Germany

Pablo Umaña

Roche Pharmaceutical Research and Early Development

Oncology Discovery & Translational Area

Roche Innovation Center Zurich

Wagistrasse 18

CH-8952 Schlieren

Switzerland

Thomas Valerius

Christian-Albrechts-University Kiel

Division of Stem Cell Transplantation and Immunotherapy

Department of Medicine

Schittenhelmstr 12

Kiel

Germany

Javier Puente Vázquez

Hospital Clínico San Carlos

Medical Oncology Department

C/Profesor Mart{í}n Lagos S/N

Madrid 28040

Spain

Penelope Ward

PWG Consulting (Biopharma) Ltd

Foxborough

Swallowfield

UK

Michael Wenger

Pharma Development Oncology

Genentech, Inc.

DNA Way

South San Francisco

CA 94080

USA

Maria Wiekowski

Novartis

1 Health Plaza

East Hanover

NJ 07936

USA

Sonja Wilke

mAb-factory GmbH

Gelsenkirchenstr 5

Braunschweig

Germany

Matthew Zibelman

Temple Fox Chase Cancer Center

Department of Medical Oncology

Cottman Avenue

Philadelphia

PA

Robert E. Zoubek

Formycon AG

Fraunhoferstr 15

Martinsried

Germany

Abbreviations