Therapeutic Monoclonal Antibodies E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 2192

Veröffentlichungsjahr: 2011

Beschreibung

* 70-chapter authoritative reference that covers therapeutic monoclonal antibody discovery, development, and clinical applications while incorporating principles, experimental data, and methodologies. * First book to address the discovery and development of antibody therapeutics in their entirety. * Most chapters contain experimental data to illustrate the principles described in them. * Authors provide detailed methodologies that readers can take away with them and use in their own laboratories.

Leseprobe

CONTENTS

FOREWORD

PREFACE

CONTRIBUTORS

PART I ANTIBODY BASICS

1. Therapeutic Monoclonal Antibodies: Past, Present, and FutureWilliam R. Strohl

1.1 Introduction

1.2 Historical Aspects

1.3 Technologies Leading To The Current Monoclonal Antibody Engineering Environment

1.4 From Biotechnology To Biopharma

1.5 Challenges and Opportunities For Monoclonal Antibodies and Fc Fusion Proteins

1.6 Summary, and “Where Do We Go From Here”?

References

2. Antibody Molecular StructureRobyn L. Stanfield and Ian A. Wilson

2.1 Introduction

2.2 General Structural Features

2.3Canonical Conformations

2.4Fab Conformational Changes

2.5 Human Anti-Hiv-1 Antibodies

2.6 Shark and Camel Antibodies

2.7 Summary

Acknowledgments

References

3. Glycosylation of Therapeutic IgGsYusuke Mimura, Roy Jefferis, Yuka Mimura-Kimura, Jodie Abrahams, and Pauline M. Rudd

Abbreviations

3.1Introduction

3.2Olig0Saccharide Structure and Heterogeneity

3.3 Assembly and Processing of N-Linked Olig0Saccharides On Igg

3.4 Glycan Analysis of Igg By High Performance Liquid Chromatography (Hplc)

3.5Preparation of Homogeneous Fc Glycoforms

3.6Influence of Fc Glycosylation On Biological Activities of Igg

3.7 Igg Glycosylation In Diseases

3.8 Conclusion

Acknowledgments

References

4. Antibody Databases and Tools: The IMGT® ExperienceMarie-Paule Lefranc

4.1 Introduction

4.2 Imgt® Standardization: Imgt-Ontology and Imgt Scientific Chart

4.3 Imgt® Genomic, Genetic, and Structural Approaches

4.4 Imgt® Databases, Tools, and Web Resources For Antibody Genomics

4.5 Imgt® Databases, Tools, and Web Resources For Antibody Genetics

4.6 Imgt® Databases, Tools, and Web Resources For Antibody Structural Analysis

4.7 Citing Imgt®

4.8 Conclusion

Acknowledgments

References

PART II ANTIBODY SOURCES

5. Human Antibodies from Transgenic MiceNils Lonberg

5.1Introduction

5.2Solutions To The Problem of Immunogenicity

5.3Genetically Engineered Mice

5.4 The Role of Immunoglobulin Genes In B-Cell Development

5.5 Human Immunoglobulin Transgenic Mice

5.6 Human Therapeutic Applications of Transgenic Mouse Derived Mabs

5.7 Summary

References

6. Rabbit HybridomaWeimin Zhu and Guo-Liang Yu

6.1 Immunology of The Rabbit

6.2 Development of Rabbit Monoclonal Antibody

6.3 Advantages of Rabbit Monoclonal Antibody

6.4 Generation of Rabbit Hybridomas

6.5 Rabmab Production

6.6 Biomarker Development Using Rabmabs

6.7 Therapeutic Rabmabs Development

6.8 Mutational-Lineage Guided (Mlg) Humanization

6.9 Summary

References

7. Human Antibody Repertoire LibrariesDavid Lowe and Tristan J. Vaughan

7.1 Introduction

7.2Historical Perspective

7.3Construction of An Scfv Library In A Phagemid Vector

7.4 Library Quality Control

7.5 Semi-Synthetic Human Antibody Repertoires

7.6Human Antibody Repertoires In Other Display Formats

7.7Summary

References

PART III IN VITRO DISPLAY TECHNOLOGY

8. Antibody Phage DisplayMichael Hust, Holger Thie, Thomas Schirrmann, and Stefan Diibel

8.1 Introduction

8.2 How Phage Display Works

8.3 Selection (Panning) of Binders

8.4Evaluation of Binders

8.5Phage Display Vectors

8.6 Phage Display Libraries

8.7 Generation of Phage Display Libraries

Acknowledgments

References

9. Yeast Surface DisplayJennifer L. Lahti and Jennifer R. Cochran

9.1 Yeast Surface Display Construct

9.2 Antibody Fragments Engineered With Yeast Surface Display

9.3 Engineering Antibodies For Affinity, Specificity, Stability, and Expression

9.4 Generating Yeast-Displayed Antibody Libraries

9.5 Screening Yeast-Displayed Antibody Libraries

9.6 Applications of Yeast Surface Display

9.7 Summary

Acknowledgments

References

10. Ribosomal DisplayGeorge Thorn

10.1 Introduction

10.2 Materials

10.3 Methods

10.4 Summary

References

11. Bacterial Display of AntibodiesThomas J. Van Blarcom and Barrett R. Harvey

11.1 Introduction

11.2 Systems For Gram-Negative Bacteria

11.3 Systems For Gram-Positive Bacteria

11.4 Summary

Acknowledgments

References

12. Antibody Selection from Immunoglobulin Libraries Expressed in Mammalian CellsErnest S. Smith and Maurice Zauderer

12.1 Introduction

12.2 Immunoglobulin Expression Libraries Constructed In A Poxvirus Vector For Expression In Mammalian Cells

12.3 Selection of Antibodies In Secreted Igg Format

12.4 Membrane Antibody Platform

12.5 Advantages of Antibody Selection From Immunoglobulin Libraries Expressed In Mammalian Cells

Acknowledgments

References

PART IV ANTIBODY ENGINEERING

13. Antibody Engineering: Humanization, Affinity Maturation, and Selection TechniquesJuan C. Almagro and William R. Strohl

13.1 Introduction

13.2 Humanization Methods

13.3 Affinity Maturation

13.4 Selection Techniques

13.5 Future Directions

References

14. Modulation of Serum Protein Homeostasis and Transcytosis by the Neonatal Fc ReceptorWilliam F. Dall'Acqua and Herren Wu

14.1 Modulating The Serum Half-Life and Transcytosis of Antibodies

14.2 Homeostatic Regulation of Albumin

Acknowledgments

References

15. Engineering the Antibody Fc Region for Optimal Effector FunctionGreg A. Lazar and John R. Desjarlais

15.1 Introduction

15.2 Anatomy of The Fc Region

15.3 Engineering Fc For Improved Affinity To FcγRs

15.4 Complement

15.5 Effector Function Silent Fc Regions

15.6 Summary and Future Directions

Acknowledgments

References

PART V PHYSIOLOGY and IN VIVO BIOLOGY

16. Antibody-Complement InteractionKileen L. Mershon and Sherie L. Morrison

16.1 Discovery of Complement

16.2 The Three Pathways of Complement and Their Functions

16.3Activities of Complement

16.4Regulation of Complement

16.5 Antibody-Dependent Complement Activation

16.6 Summary

References

17. Bacteria Immunoglobulin-Binding Proteins: Biology and Practical ApplicationsLeslie Cope and Tessie McNeely

17.1 Introduction

17.2 Ibp: Biological Function and Structure

17.3 Early Scientific Uses

17.4 Immunoglobulin Purification

17.5 Cell Isolation Techniques

17.6 Ibp Expression By Heterologous Microbes

17.7Fusion Proteins

17.8Spa-Derived Affibody

17.9Proteomics

17.10Clinical Applications

17.11SpaTyping

17.12 Summary

References

18. Immunogenicity Screening Using in Silico Methods: Correlation between T-Cell Epitope Content and Clinical Immunogenicity of Monoclonal AntibodiesSi-Han Hai, Julie A. McMurry, Paul M. Knopf William Martin, and Anne S. De Groot

18.1 Introduction

18.2 Comparative Td Immunogenicity of Different Monoclonal Antibodies

18.3 Immunogenic Effects of Monoclonal Antibodies

18.4 T-Cell Epitope Prediction

18.5 Confirmation of Predicted T-Cell Epitopes

18.6 Application: Prospective Prediction of Immunogenicity

18.7 Incorporating T-Cell Immunogenicity Screening Into The Development Pipeline

18.8 Summary

References

19. Monoclonal Antibody Pharmacokinetics and PharmacodynamicsChristopher R. Gibson, Punam Sandhu, and William D. Hanley

19.1 Introduction: Pharmacokinetics and Pharmacodynamics In Drug Development

19.2 Pharmacokinetics of Monoclonal Antibodies

19.3 Preclinical To Clinical Pharmacokinetic Comparison

19.4 Noncompartmental Analysis

19.5 Pharmacokinetic/Pharmacodynamic Relationships

19.6 Drug-Drug Interactions

Acknowledgments

References

20. Biodistribution and ImagingTove Olaf sen and Anna M. Wu

20.1 Introduction

20.2 Improving Antibody Pharmacokinetics (Pk) For Immunopet

20.3 Applications of Immunopet In Oncology

20.4 Summary

References

21. Antibodies and the Blood-Brain BarrierAngela R. Jones and Eric V. Shusta

21.1 Introduction

21.2 Architecture of The Bbb

21.3 Intrinsic Antibody Transport At The Bbb

21.4 Antibody Modifications For Improving The Transport of Non-Bbb Targeting Antibodies

21.5 Invasive Modes For Improving Antibody Delivery

21.6 Noninvasive Modes For Improving Antibody Delivery

21.7 Antibodies For Secondary Targeting To Site(S) of Action Within The Central Nervous System

21.8 Immunization For AlzheimerʼS Disease

21.9 Summary

Acknowledgments

References

PART VI ANTIBODY CHARACTERIZATION

22. Determination of Equilibrium Dissociation ConstantsRobin E. Ernst, Katrina N. High, Tom R. Glass, and Qinjian Zhao

22.1 Introduction

22.2 Kinetic-Based Dissociation Constant Determination By Spr-Based Technology

22.3 Equilibrium-Based Dissociation Constant Determination By Fluorescence Elisa (Fl-Elisa)

22.4 Equilibrium-Based Dissociation Constant Determination By Kinexa

22.5 Equilibrium Dissociation Constant Determination For Igg To Whole Cells

22.6 Precautions and Artifacts In KD Determination

22.7 Conclusion

23. Molecular and Functional Characterization of Monoclonal AntibodiesQinjian Zhao, Terrance A. Stadheim, Lorenzo Chen, and Michael W. Washabaugh

23.1 Introduction

23.2 Molecular Structural Analysis of Mab By Physicochemical Methods

23.3 Glycosylation and Glycan Analysis

23.4 Molecular Heterogeneity

23.5 Functional Analyses of Mab Candidates

23.6 Summary and Concluding Remarks

Acknowledgments

References

24. Characterization of Heterogeneity in Monoclonal Antibody ProductsYang Wang, Michael W. Washabaugh, and Qinjian Zhao

24.1 Introduction

24.2 Heterogeneity of Mab: How It Is Formed and What Makes It Worse

24.3 Nature of Heterogeneity In Mab Products

24.4 Analysis of Charge-Related Heterogeneity

24.5 Analysis of Molecular Heterogeneity Related To Size

24.6 Conclusion

References

PART VII ANTIBODY EXPRESSION

25. Antibody Expression in Mammalian CellsFubao Wang, Lorenzo Chen, Neal Connors, and Henryk Mach

25.1 Introduction

25.2 Vectors For Immunoglobulin Expression

25.3 Antibody Production By Transient Expression

25.4 Purification of Transiently Expressed Antibodies

25.5 Analytical and Biophysical Characterization of Purified Antibodies

References

26. Production of Antibodies in Pichia pastorisJuergen H. Nett

Abstract

26.1 Introduction

26.2 Examples of Antibody Expression In Pichia Pastoris

26.3 Summary

References

27. Production of Antibody Fab' Fragments in E. coliDavid P. Humphreys and Leigh Bowering

27.1 Introduction

27.2Description of Antibody Fab′ Fragments

27.3Effect of Antibody Sequence and Stability On Expression

27.4 Expression Alternatives

27.5 Expression Vectors

27.6Expression of Multimeric Fab′ Proteins

27.7Influence of The Host Environment: Strain Selection and Improvement

27.8 Engineered Functionality of Fab′ Fragments

27.9 Media Effects

27.10 Extraction of Proteins From The Periplasm

27.11 Expression Methods

27.12 Recovery and Purification

27.13 Quality Issues

27.14 Summary and Perspectives

References

28. Production of Human Therapeutic Monoclonal Antibodies in Chicken EggsLei Zhu and Robert J. Etches

28.1Introduction

28.3 Evolution of Transgenic Technology In Chickens

28.4 Production of Mab Fragments In Transgenic Chickens Made By Retroviral Vectors and Its Limitations

28.5 Production of Complete Mab Molecules In Chimeric Chickens Made By Ces Cell-Mediated Technology

28.6 Other Transgenic Systems, Advantages of The Transgenic Chicken System, and Its Future Outlook For The Production of Mab In Eggs

28.7 Summary

Acknowledgments

References

29. Production of Antibodies in PlantsKevin M. Cox, Jeffrey T. Regan, Jason D. Sterling, Vincent P. M. Wingate, and Lynn F. Dickey

29.1Introduction

29.2Plant Derived Mabs As Pharmaceutical Agents

29.3Plant Transformation Approaches

29.4Benefits of Plant-Based Antibody Expression

29.5 Production of Plant-Made Antibodies

29.6 Plant Secretory Pathway

29.7 N-Glycan Optimization of Plant-Derived Mabs

29.8 Enhanced Fc Functionality of Glyco-Optimized Mabs

29.9O-Glycosylation of Plant-Derived Mabs

29.10Summary

References

PART VIII THERAPEUTIC ANTIBODIES

30. The Formulation and Delivery of Monoclonal AntibodiesVikas K. Sharma, Hung-Wei Chih, Randall J. Mrsny, and Ann L. Daugherty

30.1 Introduction

30.2 Formulation Development of Monoclonal Antibodies

30.3 Novel Delivery of Monoclonal Antibodies

30.4 Conclusions: Challenges and Opportunities

Acknowledgments

References

31. Therapeutic Antibodies in Clinical Use and Leading Clinical CandidatesNingyan Zhang, Brent R. Williams, Ping Lu, Zhiqiang An, and Chen-Ni Chin

31.1 Approved Therapeutic Mabs In Oncology

31.2 Approved Therapeutic Mabs For The Treatment of Autoimmune and Inflammatory Disorders (Aiid)

31.3 Approved Therapeutic Mabs For Infectious Diseases, Respiratory and Cardiovascular Disorders

31.4 Therapeutic Antibodies In Clinical Phase Iii Trials For Oncology

31.5 Therapeutic Antibodies In Clinical Phase Iii Trials In Aiid, Infectious Diseases, and Other Disorders

31.6 Market Outlook

Acknowledgments

References

32. Follow-On Protein Products: What, Where, When, How?Brent R. Williams and William R. Strohl

32.1 Introduction

32.2 Regulatory Landscape

32.3 Case Studies: Currently Marketed Fopps

32.4 Discussion/Prospective

References

33. Monomeric Fc Fusion Moleculesjennifer A. Dumont, Susan C. Low, Robert T. Peters, and Alan J. Bitonti

33.1Introduction

33.2Neonatal Fc Receptor

33.3 Fcrn For Delivery of Fc-Fusion Monomers and Dimers

33.4 Epofc Monomer and Dimer Prototype Molecules

33.5 Other Monomeric Fc Fusion Proteins

33.6 Summary

Acknowledgments

References

34. Radioimmunotherapy: Current Status and Future DirectionsNeeta Pandit-Taskar and Chaitanya R. Divgi

34.1 Introduction

34.2 Radionuclides

34.3 Radioimmunotherapy of Lymphoma

34.4 Radioimmunotherapy For Solid Tumors

34.5 Pretargeting Strategies For Rit

34.6 Future Strategies

34.7 Conclusion

References

35. Antibody-Drug Conjugate TherapyStephen C. Alley, Dennis Benjamin, and Che-Leung Law

35.1 Introduction

35.2 The Role of Receptor-Mediated Endocytosis In Drug Delivery By Immunoconjugates

35.3 Characteristics of An Fda-Approved Immunoconjugate

35.4 Tumor Cell Surface Targets For Adcs

35.5 Drug Delivery Vehicles

35.6 The Choice of Drug

35.7 Bystander Effect

35.8 Linker Choice

35.9 Drug Conjugation Site

35.10Optimizing The Number of Drugs Per Antibody

35.11Summary

References

ABBREVIATIONS

INDEX

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Library of Congress Cataloging-in-Publication Data:

Therapeutic monoclonal antibodies: from the bench to the clinic / [edited by] Zhiqiang An.p.; cm.Includes bibliographical references and index.ISBN 978-0-470-11791-0 (cloth)1. Monoclonal antibodies—Therapeutic use. I. An, Zhiqiang, Dr.[DNLM: 1. Antibodies, Monoclonal—therapeutic use. 2. Drug Discovery.QW 575.5.A6 T398 2009]

RM282.M65T495 2009616.07′98—dc22

2008053435

FOREWORD

In the latter part of the 19th century Emil von Behring and Shibasaburo Kitasato showed that serum from human patients (or animals, typically horses) who had recovered from an infectious disease (typhus, diphtheria, etc) could be used to prevent or treat the same disease in other humans (indeed hyperimmune horse serum is still used to treat diphtheria today). Hyperimmune globulins obtained from human donors are used to treat a variety of infectious diseases today. However its use is restricted by availability and limited potency. For more than a century the widespread use of antibodies for treatment of a variety of diseases has awaited a practical method for production of specific antibodies, as well as the identification of the specific targets associated with a particular disease. Today many of those limitations have been resolved, and antibody therapy is the most active field in therapeutics.

In Köhler and Milstein’s classic 1975 Nature paper, the authors state that “the manufacture of predefined specific antibodies by means of permanent tissue culture cell lines is of general interest”, and after demonstrating convincingly that this could be accomplished by fusing (mouse) spleen cells with multiple myeloma cells, they conclude “such cells can be grown in vitro in massive cultures to provide specific antibody” and “such cultures could be valuable for medical and industrial use”. Today, we can attest to the validity of those prescient remarks. It unleashed an avalanche of scientific and commercial interest. In my view it represented, in both practical and heuristic terms, the most significant methodological advance toward the treatment (not to mention diagnosis and prevention) of human disease in the past century. It initiated the era of biological therapeutics.

The first antibody for clinical use (OKT3), for tissue rejection, was approved 11 years after the Köhler and Milstein paper. Initially the field developed slowly-partially because of the time required to develop methods for “humanizing” the mouse monoclonals and to develop manufacturing processes and capability, but also significantly because of the widely held view by many pharmaceutical scientists/executives that antibodies were “transitional therapeutic products” and would be ultimately replaced by small molecules. With time it became clear that there were advantages to these macromolecules: the size could confer longer half lives, the problems of antigenicity could be limited by more effective humanization procedures. The inherent great specificity for the epitopes could be used to limit side effects, and provide progressively greater potency, and finally manufacturing processes were improving rapidly. Today, antibodies are always considered as a possible if not preferred therapeutic modality when feasible (extracellular, or cell surface targets, but also some modes for addressing intracellular targets).

In 2000, nine of the top 10 molecules were small molecule drugs and one (Epogen/Procrit) was a recombinant protein product. By 2008, the situation was dramatically different: three monoclonal antibody products (Rituxan, Remicade, and Avastin) were in the top 10, along with two other recombinant protein products (Enbrel and Epogen/Procrit). By 2014, it is predicted that five of the top 10 products will be antibodies (Avastin, Humira, Rituxan, Herceptin, and Remicade), along with two other recombinant protein products (Enbrel and Lantus). Furthermore about half of new therapeutic products under development are antibodies. It is clear that most of the high value products will be antibodies … but the largest share of the therapeutic market will be small molecules. The game is not yet over!

The opportunity for innovation exists at every level. The challenge is to develop ever increasing potency while decreasing the cost of development and production. This book comprehensively addresses the technology and the development of antibody therapeutics. It provides both basic and sophisticated information. It should be of great interest to scientists and executives in the biotech and pharmaceutical industry, and academic scientists who are interested in meeting that challenge for the benefit of healthcare, worldwide.

WILLIAM J. RUTTER

PREFACE

The study of antibodies has been a focal point in modern biology and medicine since the early 1900s. However, the ability to use antibodies as weapons against diseases or as tools to study disease state was mostly confined to crude, undefined preparations until César Milstein and Georges Köhler developed methods for the isolation of monoclonal antibodies from hybridoma cells in 1975. Since then, antibodies have not only been used as subjects and tools for breakthrough basic research, but have also been used as clinical diagnostics, reagents for high throughput drug screening, and most importantly, as life-saving medicines.

Progress in the therapeutic antibody field was initially slow and intermittent. The first therapeutic antibody, murine-derived Murononab OKT3 for acute organ rejection, was approved by the FDA in 1986, more than a decade after the discovery of the hybridoma technology. As a result of technological breakthroughs in the 1980s and 1990s, progress in the therapeutic antibody field accelerated dramatically (Chapter 1). This book provides readers with a comprehensive review of the history and tools of discovery, development, characterization, and clinical application of therapeutic antibodies.

An antibody contains two light chains and two heavy chains, which are linked by multiple disulphide bonds (Chapter 2). The antigen-binding complementarity-determining regions (CDRs) are short, hypervariable amino acid sequences found in the variable domains of both light and heavy chains. The binding affinity and specificity of an antibody to its antigen can be readily manipulated by in vitro genetic engineering approaches (Chapter 13). Powerful bioinformatics tools are being developed to annotate the genetic diversity of antibodies (Chapter 4).

After binding to a target, the fragment crystallizable region (Fc region) of an antibody can recruit effector cells such as natural killer cells, macrophages, or neutrophils, and/or activate the complement system to destroy the target-associated cells. These properties, referred to as “antibody-dependent cell cytotoxicity” (ADCC) and “complement-dependent cytotoxicity” (CDC), respectively, are fundamental aspects of natural antibody biology that are being manipulated to create therapeutics with more potent biological activities (Chapter 16). In addition to ADCC and CDC activities, the Fc region of an antibody is also responsible for the long half-life of the molecule through its interaction with the neonatal receptor FcRn (Chapter 19). Finally, the Fc domain has interactions with certain bacterial proteins such as Protein A/G, which demonstrate the power of evolution in the interaction between microorganisms and the molecules made by the body to defend against them (Chapter 17).

Like many other mammalian proteins, antibodies are glycoproteins. Glycosylation plays an important role in the biological activities of antibodies and manipulation of the glycosylation pattern of an antibody has been applied to the improvement of pharmaceutical properties of the molecule (Chapters 3 and 26). Genetic manipulation of the Fc region of an antibody has also been utilized to improve the serum half-life, ADCC, and CDC activities of the molecule (Chapters 14 and 15).

One of the major sources of therapeutic antibodies is monoclonal antibodies isolated from immunized animals using hybridoma technology (Chapters 5 and 6). Monoclonal antibodies isolated from wild-type animals, such as murine species, induce immunological responses in humans. To reduce this response, monoclonal antibodies are commonly modified and produced as murine/human chimeric antibodies or humanized antibodies for therapeutic applications (Chapters 1, 13, and 31). In addition, fully human monoclonal antibodies can be generated in transgenic mice to circumvent the immuno-genicity issue of murine sequence (Chapter 5). Phage-displayed antibody libraries represent another source of fully human antibodies (Chapters 7 and 8). In addition to phage, antibody fragments or, in some cases, full IgG molecules can also be displayed on yeast (Chapter 9), bacteria (Chapter 11), mammalian cells (Chapter 12), and on other in vitro systems such as ribosomes (Chapter 10).

Most therapeutic antibodies are full length IgG molecules (Chapter 31). In addition to IgGs, antibody fragments have also been developed as therapeutics (Chapters 27, 31, and 33) and as imaging reagents (Chapter 20). Monoclonal antibodies have been used as tissue targeting reagents as well; there are many examples of antibodies used as targeting agents for small molecule toxins (Chapter 35) or radiolabeled isotopes (Chapter 34).

The history of therapeutic antibody development parallels the desire of the industry to reduce the potential immunogenicity of the drugs. In silico tools have been developed; to analyze antibody sequences to be humanized (Chapter 4) and to predict the immunogenicity potential of antibodies before they are tested in the clinic (Chapter 18).

The manufacturing of therapeutic monoclonal antibodies has been, to date, an expensive proposition. A large scale facility can take multiple years to build, at a cost of several hundreds of million dollars. Mammalian cell culture (Chinese hamster ovary cells; CHO) is the dominant production cell platform for antibody therapeutics (Chapter 25). Other exploratory methods of antibody production include the use of plants (Chapter 29), transgenic animals (milk), eggs (Chapter 28), and yeast (Chapter 26). An antibody fragment made in a bacterial cell line was approved for clinical use in 2008 (Chapter 27).

Antibodies can engage a wide range of extracellular drug targets such as membrane bound proteins or circulating ligands and cytokines, but they do not readily cross cell membranes or the brain blood barrier (BBB). Efforts are being made to facilitate the transfer of antibodies across cell membranes and the BBB (Chapter 21). Unlike small-molecule drugs, monoclonal antibodies are large, complex molecules that are not easily formulated and delivered (Chapter 30). Additionally, antibody therapeutics are produced as heterogeneous mixtures of molecules including different glycoforms that can vary slightly in molecular structure (Chapter 24). Complex analytical tools have been developed and optimized for the molecular and functional characterization of antibody therapeutics (Chapters 22, 23, and 24).

The complex nature of antibodies, as mentioned above, has contributed to the lack of a consensus regarding the definition of generic biopharmaceuticals. Multiple terms are used to describe generic biopharmaceuticals, such as biogenerics, biosimilars, and follow-on biologies (Chapter 32). The development of follow-on (or biosimilar) antibody therapeutics will be expensive as compared with small molecule generics, as it is highly likely that regulatory authorities will require that clinical trials be run to provide comparability data. Experts predict that it will take at least a decade before technology is advanced to a stage whereby the safety and bioequivalence of a biosimilar can be verified without clinical testing. Despite the regulatory and technological barriers to the development of generic biopharmaceuticals, it is certain that therapeutic antibodies will eventually face “generic” competition.

It seems fitting that this book should be written a hundred years after Paul Ehrlich received the Nobel Prize in 1908 for his studies in medicine, hematology, immunology, and chemotherapy. It was Ehrlich who popularized the term “magic bullet” which was an apt and prescient description for many of the therapeutic monoclonal antibodies on the market or in development today.

In closing, I would like to express my gratitude to Ms. Anita Lekhwani for the opportunity to edit this book and I am indebted to the expert authors who contributed to this endeavor. I want to thank Dr. William R. Strohl for his input on the project. I also want to thank Mr. Nick Barber for his assistance during the production stage of the project and Ms. Michelle Snider for typing the index words. Finally, I want to thank my family for their patience and support throughout this complex undertaking.

ZHIQIANG AN

CONTRIBUTORS

Jodie Abrahams, National Institute for Bioprocessing Research and Training, Belfield, Dublin, Ireland

Stephen C. Alley, Seattle Genetics, Inc., Bothell, WA

Juan C. Almagro, Centocor R&D, Inc., Radnor, PA

Zhiqiang An, Epitomics, Burlingame, CA

Dennis Benjamin, Seattle Genetics, Inc., Bothell, WA

Alan J. Bitonti, Syntonix Pharmaceuticals, Waltham, MA

Leigh Bowering, UCB-Celltech, Slough, Berkshire, UK

Lorenzo Chen, Merck Research Laboratories, West Point, PA

Hung-Wei Chih, Genentech, Inc., South San Francisco, CA

Chen-Ni Chin, Merck Research Laboratories, West Point, PA

Jennifer R. Cochran, Stanford University, Stanford, CA

Neal Connors, Merck Research Laboratories, Rahway, NJ

Leslie Cope, Merck Research Laboratories, West Point, PA

Kevin M. Cox, Biolex Therapeutics, Pittsboro, NC

William F. Dall–Acqua, MedImmune, Inc., Gaithersburg, MD

Ann L. Daugherty, Genentech, Inc., South San Francisco, CA

Anne S. De Groot, Brown University and EpiVax, Inc., Providence, RI

John R. Desjarlais, Xencor, Inc., Monrovia, CA

Lynn F. Dickey, Biolex Therapeutics, Pittsboro, NC

Chaitanya R. Divgi, University of Pennsylvania, Philadelphia, PA

Stefan Dübel, Technical University of Braunschweig, Braunschweig, Germany

Jennifer A. Dumont, Syntonix Pharmaceuticals, Waltham, MA

Robin E. Ernst, Merck Research Laboratories, West Point, PA

Robert J. Etches, Origen Therapeutics, Burlingame, CA

Christopher R. Gibson, Merck Research Laboratories, West Point, PA

Tom R. Glass, Sapidyne Instruments Inc., Boise, Idaho

Si-Han Hai, Brown University, Providence, RI

William D. Hanley, Merck Research Laboratories, West Point, PA

Barrett R. Harvey, The University of Texas Health Sciences Center, Houston, TX

Katrina N. High, Merck Research Laboratories, West Point, PA

David P. Humphreys, UCB-Celltech, Slough, Berkshire, UK

Michael Hust, Technical University of Braunschweig, Braunschweig, Germany

Roy Jefferis, University of Birmingham, Edgbaston, Birmingham, UK

Angela R. Jones, University of Wisconsin, Madison, WI

Paul M. Knopf, Brown University and EpiVax, Inc., Providence, RI

Jennifer L. Lahti, Stanford University, Stanford, CA

Greg A. Lazar, Xencor, Inc., Monrovia, CA

Che-Leung Law, Seattle Genetics, Inc., Bothell, WA

Marie-Paule Lefranc, Institut de Génétique Humaine, Montpellier, France

Nils Lonberg, Medarex, Milpitas, California

Susan C. Low, Syntonix Pharmaceuticals, Waltham, MA

David Lowe, MedImmune Limited, Granta Park, Cambridge, UK

Ping Lu, Merck Research Laboratories, West Point, PA

Henryk Mach, Merck Research Laboratories, West Point, PA

William Martin, EpiVax, Inc., Providence, RI

Julie A. McMurry, EpiVax, Inc., Providence, RI

Tessie McNeely, Merck Research Laboratories, West Point, PA

Kileen L. Mershon, University of California, Los Angeles, CA

Yusuke Mimura, NHO Yamaguchi-Ube Medical Center, Ube, Japan

Yuka Mimura-Kimura, National Institute for Bioprocessing Research and Training, Belfield, Dublin, Ireland

Sherie L. Morrison, University of California, Los Angeles, CA

Randall J. Mrsny, Genentech, Inc., South San Francisco, CA

Juergen H. Nett, GlycoFi, Inc., Lebanon, NH

Tove Olafsen, University of California, Los Angeles, CA

Neeta Pandit-Taskar, Memorial Sloan-Kettering Cancer Center, New York, NY

Robert T. Peters, Syntonix Pharmaceuticals, Waltham, MA

Jeffrey T. Regan, Biolex Therapeutics, Pittsboro, NC

Pauline M. Rudd, National Institute for Bioprocessing Research and Training and Conway Institute, University College Dublin, Belfield, Dublin, Ireland

Punam Sandhu, Merck Research Laboratories, West Point, PA

Thomas Schirrmann, Technical University of Braunschweig, Braunschweig, Germany

Vikas K. Sharma, Genentech, Inc., South San Francisco, CA

Eric V. Shusta, University of Wisconsin, Madison, WI

Ernest S. Smith, Vaccinex, Inc., Rochester, NY

Terrance A. Stadheim, GlycoFi, Inc., Lebanon, NH

Robyn L. Stanfield, The Scripps Research Institute, La Jolla, CA

Jason D. Sterling, Biolex Therapeutics, Pittsboro, NC

William R. Strohl, Centocor R&D, Inc., Radnor, PA

Holger Thie, Technical University of Braunschweig, Braunschweig, Germany

George Thom, MedImmune Limited, Granta Park, Cambridge, UK

Thomas J. Van Blarcom, University of Texas at Austin, Austin, Texas

Tristan J. Vaughan, MedImmune Limited, Granta Park, Cambridge, UK

Fubao Wang, Merck Research Laboratories, West Point, PA

Yang Wang, Merck Research Laboratories, West Point, PA

Michael W. Washabaugh, Merck Research Laboratories, West Point, PA

Vincent P. M. Wingate, Biolex Therapeutics, Pittsboro, NC

Brent R. Williams, Merck Research Laboratories, West Point, PA

Ian A. Wilson, The Scripps Research Institute, La Jolla, CA

Anna M. Wu, University of California, Los Angeles, CA

Herren Wu, MedImmune, Inc., Gaithersburg, MD

Guo-Liang Yu, Epitomics, Burlingame, CA

Maurice Zauderer, Vaccinex, Inc., Rochester, NY

Ningyan Zhang, Merck Research Laboratories, West Point, PA

Qinjian Zhao, Merck Research Laboratories, West Point, PA

Lei Zhu, Origen Therapeutics, Burlingame, CA

Weimin Zhu, Epitomics, Burlingame, CA

PART I

ANTIBODY BASICS

CHAPTER 1

Therapeutic Monoclonal Antibodies: Past, Present, and Future

WILLIAM R. STROHL

1.1 Introduction

1.2 Historical Aspects

1.2.1 Historical Aspects: Origins of Serum Therapy, Forerunner to the Monoclonal Antibody Business

1.2.2 IVIG Therapeutics and Prophylactics

1.3 Technologies Leading to the Current Monoclonal Antibody Engineering

1.3.1 Fundamental Breakthroughs Allowing for Recombinant Monoclonal Antibodies

1.3.2 Hybridoma Technology

1.3.3 Transfectomas and Chimeric Antibodies

1.3.4 Humanization Technology

1.3.5 Humanized Mice

1.3.6 Phage Display Technology

1.3.7 Human Antibody Libraries

1.3.8 Summary of Core Therapeutic Mab Technologies Leading to Therapeutics

1.4 From Biotechnology to BioPharma

1.4.1 From OKT3®d to Remicade: Early Successes and Disappointments

1.4.2 Examples of Other Early Mabs

1.4.3 Evolution of the Biotechnology Industry to the New BioPharma Industry

1.5 Challenges and Opportunities for Monoclonal Antibodies

1.5.1 SWOT Analysis

1.5.2 Competition on “Hot” Targets

1.5.3 Targets

1.5.4 Differentiation and Fit-for-Purpose Biologies

1.6 Summary, and “Where Do We Go From Here”

References

ABSTRACT

In this chapter, an overview of the therapeutic antibody industry today, including the many commercial antibodies and Fc fusions and the rich clinical pipeline, is presented and analyzed. The long history of antibodies is given to bring context to the therapeutic antibody industry. This history includes serum therapy, the use of IVIG, and the evolution of those therapies into the development of the monoclonal antibody business as we know it today. The history of technologies that fostered the revolution of therapeutic antibody development in the 1990s is also described. Finally, the future of the therapeutic monoclonal antibody and Fc fusion business is presented along with opportunities and challenges facing the business and those who work in it.