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Contents
Cover
Related Titles
Title Page
Copyright
Preface
List of Contributors
Chapter 1: Introduction: Antibody Structure and Function
1.1 Introduction to Antibodies
1.2 General Domain and Structure of IgG
1.3 The Neonatal Fc Receptor
1.4 Introduction to FcγR- and Complement-Mediated Effector Functions
1.5 Current Trends in Antibody Engineering
References
Part One: Methods of Production for Fc-Fusion Proteins
Chapter 2: Fc-Fusion Protein Expression Technology
2.1 Introduction
2.2 Expression Systems Used for Fc-Fusion Proteins
2.3 Summary
References
Chapter 3: Cell Culture-Based Production
3.1 Introduction
3.2 Basic Aspects of Industrial Cell Culture
3.3 Specific Process Considerations for Fc-Fusion Molecules
3.4 Case Studies
3.5 Conclusions
References
Chapter 4: Downstream Processing of Fc-Fusion Proteins
4.1 Introduction and Overview of Fc-Fusion Proteins
4.2 Biochemistry of Fc-Fusion Proteins
4.3 Purification of Fc-Fusion Proteins from Mammalian Cells
4.4 Purification of Fc-Fusion Protein from Microbial Systems
4.5 Future Innovations in Fc-Fusion Protein Downstream Processing
4.6 Conclusions
References
Chapter 5: Formulation, Drug Product, and Delivery: Considerations for Fc-Fusion Proteins
5.1 Challenges of Molecule Design and Protein Formulation
5.2 The Promise of Fc-Fusion Proteins
5.3 Current Landscape of Commercial Antibody-Related Products
5.4 Fc Conjugates Compared to mAb Counterparts
5.5 Factors in Selecting Liquid versus Lyophilized Formulations
5.6 Advantages and Disadvantages of a Lyophilized Product
5.7 The General Lyophilization Formulation Strategy for Fc-Fusion Proteins
5.8 Bulking Agent
5.9 Surfactant
5.10 The Impact of Residual Moisture
5.11 Practical Considerations for Low-Protein-Concentration Lyophilized Products
5.12 Drug Delivery Considerations
5.13 Device Considerations
5.14 Assessing Feasibility of a Multidose Formulation
5.15 Overage Considerations
5.16 Summary
References
Chapter 6: Quality by Design Applied to a Fc-Fusion Protein: A Case Study
6.1 Introduction
6.2 Critical Quality Attributes
6.3 Critical Process Parameters
6.4 Process Characterization
6.5 Global Multistep Design Space
6.6 Robustness Studies
6.7 Adaptive Strategy
6.8 Engineering Design Space
6.9 Control Strategy
6.10 Continuous Process Verification
6.11 Expanded Change Protocol and Continual Improvement
6.12 Business Case
References
Chapter 7: Analytical Methods Used to Characterize Fc-Fusion Proteins
7.1 Background
7.2 Product Characterization
7.3 Characterization of the Reference Standard
7.4 Typical Product Release and Stability Assays
7.5 Analytical Method Qualification and Validation
References
Part Two: Case Studies of Therapeutic Fc-Fusion Proteins
Chapter 8: Introduction to Therapeutic Fc-Fusion Proteins
8.1 Therapeutic Fc-Fusion Proteins
8.2 Background
8.3 Fc-Fusion Constructs Have Increased In Vivo Stability
8.4 Immunoglobulin-Mediated Effector Function
8.5 Considerations in Fc-Fusion Protein Design
8.6 Fc-Fusion Proteins Approved for Use in the United States
8.7 Concluding Remarks
References
Chapter 9: Alefacept
9.1 Introduction
9.2 Chronic Plaque Psoriasis
9.3 Conventional Treatments for Psoriasis
9.4 Preclinical Development
9.5 Preclinical Primate Studies
9.6 Phase 1 and 2 Human Clinical Studies
9.7 Phase 3 Studies
9.8 Clinical Pharmacology
9.9 Clinical Safety
9.10 Amevive Discontinued
References
Chapter 10: Etanercept
10.1 Introduction
10.2 Design, Construction, and Characterization of TNFR-Fc-Fusion Protein
10.3 Etanercept Preclinical Development
10.4 Etanercept Key Clinical Trials
10.5 Competitive Landscape
10.6 Conclusions
References
Chapter 11: Abatacept and Belatacept
11.1 Introduction
11.2 Design, Construction, and Characterization of Abatacept
11.3 Immunosuppressive Properties of Abatacept
11.4 Rational Design and Characterization of Belatacept
11.5 Belatacept Activity in Primate Renal Transplant Studies
11.6 Abatacept Clinical Development
11.7 Belatacept Clinical Development
11.8 Concluding Remarks
References
Chapter 12: Aflibercept
12.1 Introduction
12.2 Clinical Indications
12.3 Characterization of Aflibercept
12.4 Preclinical Studies with Aflibercept
12.5 Clinical Studies with Aflibercept
12.6 Summary
References
Chapter 13: Recombinant Factor VIII– and Factor IX–Fc Fusions
13.1 Introduction
13.2 Structure and Function of Factor IX and Factor VIII
13.3 Rationale and Design of rFIXFc- and rFVIIIFc-Fusion Proteins
13.4 Development of a Clinical Candidate and Beyond
References
Index
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Print ISBN: 978-3-527-33317-2
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Cover Design Adam-Design, Weinheim, Germany
Preface
Fc-fusion proteins – engineered polypeptides that combine biologically active peptides or protein domains with the crystallizable fragment (Fc) domain of an antibody – have become widely used agents both in research and in clinical practice. The fact that these molecules resemble antibodies in so many aspects of structure, function, expression, purification, and pharmacology has enabled them to be rapidly integrated into a variety of assays, preclinical studies, and clinical applications through leveraging the prior experience with monoclonal antibodies. In the years following the 1989 report from Genentech by Dan Capon and colleagues on an Fc-fusion protein or “immunoadhesin” composed of CD4 linked to an antibody Fc, a variety of different receptor extracellular domains were produced in this format. An earlier volume, Antibody Fusion Proteins, by Chamow and Ashkenazi (Wiley, 1999) highlighted progress up to the stage of the first therapeutic Fc fusions progressing through clinical trials. Etanercept became the first FDA-approved therapeutic fusion protein in 1998 and has since become one of the most clinically and commercially successful therapeutics. However, the story of therapeutic Fc fusions does not end here. On the contrary, a growing number of these molecules are being developed as biotherapeutics, including Fc-fusion proteins composed of heterodimeric polypeptide chains and others containing novel peptide mimotopes attached to Fc fragments. We therefore thought it important to review the literature and experience in developing this novel class of biologics – hence the current volume, Therapeutic Fc-Fusion Proteins, which brings up-to-date information on the processes of designing and producing these molecules and highlights some of the most prominent case studies from clinical experience.
Owing to the crucial components of antibody structure and function in the design, production, and use of therapeutic Fc fusions, we begin the book with an extensive introduction to the structure and function of IgG molecules (Chapter 1). This is followed by Part One, a series of chapters summarizing state-of-the-art approaches for producing therapeutic Fc proteins: Chapter 2 presents the principles of design and expression systems; Chapter 3, cell culture production; Chapter 4, downstream processing; Chapter 5, formulation and delivery; Chapter 6, quality by design; and Chapter 7, analytical characterization. These chapters provide a roadmap for the development and life cycle of manufacturing processes for therapeutic Fc fusions. Part Two begins with a synopsis (Chapter 8) of clinically significant Fc-fusion proteins that have been approved or are in late-stage clinical trials. Subsequent chapters present case studies of a subset of these, selected for their unique features in terms of molecular design and/or mechanism of action: alefacept, a lymphocyte function-associated antigen 3 (LFA-3) fusion (Chapter 9); etanercept, a tumor necrosis factor (TNF) receptor fusion (Chapter 10); abatacept and belatacept, cytotoxic T-lymphocyte antigen 4 (CTLA-4) fusions (Chapter 11); aflibercept, a vascular endothelial growth factor (VEGF) receptor fusion (Chapter 12); and factor VIII/IX fusions (Chapter 13). In several cases, we have included authors who were involved directly in development of the Fc-fusion protein products about which they have written. We believe that these accounts of the biologics development process in the context of a range of biological mechanisms and disease indications provide important lessons for the development of future therapeutic Fc-fusion proteins.
We thank all of the contributors to this book for taking the time to write what we hope you will find are useful discussions of these topics. We also thank Laura Shih, Wendy Lin, and Anne Chassin du Guerny and the editorial staff of Wiley-Blackwell for their editing support.
| San Mateo, CA |
Steven M. Chamow |
| El Granada, CA |
Henry Lowman |
| Lexington, MA |
Thomas Ryll |
| Santa Fe, NM |
Deborah Farson |
November 2013
List of Contributors
Judy R. Berlfein
Biogen Idec
Hemophilia Research
14 Cambridge Center
Cambridge, Massachusetts 02142
USA
Jody D. Berry
BD Biosciences
Antibody Discovery
10770 North Torrey Pines Road
La Jolla, California 92037
USA
Hervé Broly
Merck Serono SA – Corsier sur Vevey
Department of Biotech Process Sciences
Zone Industrielle B
1809 Fenil sur Corsier
Switzerland
Wenjin Cao
Amgen, Inc.
Drug Product Development
1 Amgen Center Drive
Thousand Oaks, California 91320
USA
Steven M. Chamow
Chamow & Associates, Inc.
San Mateo, California 94403
USA
Javier Chaparro-Riggers
Rinat-Pfizer Inc.
Protein Engineering Department
230 E. Grand Avenue
South San Francisco, California 94080
USA
Alex Eon-Duval
Merck Serono SA – Corsier sur Vevey
Department of Biotech Process Sciences
Zone Industrielle B
1809 Fenil sur Corsier
Switzerland
Deborah A. Farson
FarsonInk
Santa Fe, New Mexico 87505
USA
Janean Fisher
BD Biosciences
Antibody Discovery
10770 North Torrey Pines Road
La Jolla, California 92037
USA
Ralf Gleixner
F. Hoffmann-La Roche Ltd
Grenzacherstr. 124
4070 Basel
Switzerland
Uwe Gottschalk
Sartorius-Stedim Biotech
August-Spindler-Str. 11
37079 Goettingen
Germany
Johanna Grossman
San Francisco, California 94123
USA
Yao-Ming Huang
Biogen Idec
BioProcess Development
5000 Davis Drive Research Triangle Park, NC 27709
USA
Esohe Idusogie
OncoMed Pharmaceuticals
800 Chesapeake Drive
Redwood City, California 94063
USA
Rashmi Kshirsagar
Biogen Idec
BioProcess Development
14 Cambridge Center
Cambridge, Massachusetts 02142
USA
Angela L. Linderholm
Davis, California 95616
USA
Ella Mendoza
BD Biosciences
Antibody Discovery
10770 North Torrey Pines Road
La Jolla, California 92037
USA
Massimo Morbidelli
Institute for Chemical and Bioengineering
Department of Chemistry and Applied Biosciences
ETH Zurich
Wolfgang-Pauli-Strasse 10
8093 Zurich
Switzerland
Michael Mulkerrin
OncoMed Pharmaceuticals
800 Chesapeake Drive
Redwood City, California 94063
USA
Benjamin Neunstoecklin
Institute for Chemical and Bioengineering
Department of Chemistry and Applied Biosciences
ETH Zurich
Wolfgang-Pauli-Strasse 10
8093 Zurich
Switzerland
Robert J. Peach
Receptos, Inc.
10835 Road to the Cure, Suite #205
San Diego, California 92121
USA
Robert T. Peters
Biogen Idec
Hemophilia Research
14 Cambridge Center
Cambridge, Massachusetts 02142
USA
Deirdre Murphy Piedmonte
Amgen, Inc.
Drug Product Development
1 Amgen Center Drive
Thousand Oaks, California 91320
USA
Jaume Pons
Rinat-Pfizer Inc.
Protein Engineering Department
230 E. Grand Avenue
South San Francisco, California 94080
USA
Arvind Rajpal
Rinat-Pfizer Inc.
Protein Engineering Department
230 E. Grand Avenue
South San Francisco, California 94080
USA
Margaret Speed Ricci
Amgen, Inc.
Drug Product Development
1 Amgen Center Drive
Thousand Oaks, California 91320
USA
Thomas Ryll
Biogen Idec
BioProcess Development
14 Cambridge Center
Cambridge, Massachusetts 02142
USA
Abhinav A. Shukla
KBI Biopharma
1101 Hamlin Road
Durham, North Carolina 27704
USA
Miroslav Soos
Institute for Chemical and Bioengineering
Department of Chemistry and Applied Biosciences
ETH Zurich
Wolfgang-Pauli-Strasse 10
8093 Zurich
Switzerland
Pavel Strop
Rinat-Pfizer Inc.
Protein Engineering Department
230 E. Grand Avenue
South San Francisco, California 94080
USA
Dwayne Stupack
University of California
Department of Reproductive Medicine
San Diego, California 92093
USA
Pascal Valax
Merck Biodevelopment Site Montesquieu 1 Rue Jacques Monod 33650 Martillac France
Barbara Woppmann
Biogen Idec
BioProcess Development
14 Cambridge Center
Cambridge, Massachusetts 02142
USA
Catherine Yang
BD Biosciences
Antibody Discovery
10770 North Torrey Pines Road
La Jolla, California 92037
USA
Ping Y. Yeh
Amgen, Inc.
Drug Product Development
1 Amgen Center Drive
Thousand Oaks, California 91320
USA
Yik Andy Yeung
Rinat-Pfizer Inc.
Protein Engineering Department
230 E. Grand Avenue
South San Francisco, California 94080
USA
Shanique Young
University of California
Department of Reproductive Medicine
San Diego, California 92093
USA
