Librería Servicio Médico

Author : M. Chamow / Ryll / B. Lowman / Farson 

Language: English

Finishing : Hardcover, 400 pages

ISBN : 978-3-527-33317-2

Edition Number: 2014

Author Information:

Steven M. Chamow, PhD is currently the principal at Chamow & Associates, Inc., a biopharmaceutical consulting firm. He has developed protein therapeutics for 26 years and contributed to the development of three marketed products (Avastin, Natrecor, Vectibix). He began his career in process development at Genentech, Inc. and has served in management and executive roles at several other biotechnology companies. He is author or co-author of more than 45 scientific publications and patents and co-editor of a 1999 book entitled Antibody Fusion Proteins. Educated at the University of California and trained at the National Institutes of Health, he lives in San Mateo, CA with his wife.

Thomas Ryll, PhD currently serves as Senior Director of Cell Culture Development at Biogen Idec in Cambridge, MA. He has contributed to the development of several marketed products, including Rituxan, Raptiva, Vectibix, Eloctate and Alprolix. He began his career at Genentech, Inc. as scientist in process development. Since then, he served in various scientific and management roles with increasing responsibilities at Abgenix, Inc., Tanox Inc., and Biogen Idec, Inc. Educated at the Technical University of Braunschweig in Germany, he is author or co-author of more than 35 scientific publications and patents. He lives in Lexington, MA with his family.

Henry B. Lowman, PhD currently serves as Chief Scientific Officer at CytomX Therapeutics, Inc. Dr. Lowman served a 20-year tenure at Genentech, Inc., where he focused on protein and antibody therapeutics. His career interests include structure-based protein design, structure-function analysis, and molecular diversity techniques. Dr. Lowman is an author on more than 60 scientific publications, inventor on more than 60 issued patents, and an editorial board member for the antibody journal mAbs. Dr. Lowman earned his B.A. in chemistry at Johns Hopkins University and PhD in chemistry at Purdue University.

Deborah Farson is the principal at FarsonInk, a scientific, medical writing firm. Deborah Farson
worked as a cell biologist at Cell Genesys, Inc. for 19 years. As a Senior Director of Research and Development, Deborah Farson was responsible for the development and characterization of cell lines for use as immunotherapy products. In addition, her department developed cell lines for use in assay development and for production of recombinant proteins and antibodies. She is an author or co-author on 16 peer-reviewed journal articles and 4 issued patents. Deborah Farson currently resides in Santa Fe, NM.

Description:

Edited by three pioneers in the field – each with longstanding experience in the biotech industry – and a skilled scientific writer, this is the first book to cover every step in the development and production of immunoglobulin Fc-fusion proteins as therapeutics for human disease: from choosing the right molecular design, to pre-clinical characterization of the purified product, through to batch optimization and quality control for large-scale cGMP production.

The whole of the second part is devoted to case studies of Fc-fusion proteins that are now commercially successful products. In this section, the authors, several of whom were personally involved in clinical development of the products themselves, detail the product’s background and give insight into issues that were faced and how these issues were overcome during clinical development. This section also includes a chapter on promising new developments for the future.

An invaluable resource for professionals already working on Fc-fusion proteins and an excellent and thorough introduction for physicians, researchers, and students entering the field.

Table Of Contents:

• Preface XIII
• List of Contributors XV
• 1 Introduction: Antibody Structure and Function 1
• Arvind Rajpal, Pavel Strop, Yik Andy Yeung, and Javier Chaparro-Riggers, and Jaume Pons
• 1.1 Introduction to Antibodies 1
• 1.2 General Domain and Structure of IgG 6
• 1.2.1 Structural Aspects Important for Fc Fusion(s) 6
• 1.3 The Neonatal Fc Receptor 9
• 1.3.1 FcRn Function and Expression 9
• 1.3.2 Species Difference in FcRn 13
• 1.3.3 Engineering to Modulate Pharmacokinetics 14
• 1.4 Introduction to FcgR- and Complement-Mediated Effector Functions 16
• 1.4.1 Cell Lysis and Phagocytosis Mediation 17
• 1.4.2 FcgR-Mediated Effector Functions 17
• 1.4.3 Complement 20
• 1.4.4 Modifying Effector Functions 21
• 1.5 Current Trends in Antibody Engineering 25
• 1.5.1 Bispecific 25
• 1.5.2 Drug Conjugates 26
• References 28
• Part One Methods of Production for Fc-Fusion Proteins 45
• 2 Fc-Fusion Protein Expression Technology 47
• Jody D. Berry, Catherine Yang, Janean Fisher, Ella Mendoza, Shanique Young, and Dwayne Stupack
• 2.1 Introduction 47
• 2.2 Expression Systems Used for Fc-Fusion Proteins 50
• 2.2.1 Expression Using Mammalian Cell Lines 50
• 2.2.2 Expression Using Prokaryotic Cells 57
• 2.2.3 Expression Using Baculovirus/Insect Cells 60
• 2.3 Summary 62
• References 62
• 3 Cell Culture-Based Production 67
• Yao-Ming Huang, Rashmi Kshirsagar, and Barbara Woppmann, and Thomas Ryll
• 3.1 Introduction 67
• 3.2 Basic Aspects of Industrial Cell Culture 69
• 3.2.1 The Central Role of the Production Cell Line 69
• 3.2.2 Production Systems 70
• 3.2.3 Production Mode: Fed-Batch or Perfusion? 71
• 3.2.4 Scale-Up 73
• 3.2.5 Raw Materials and Process Control 74
• 3.2.6 How to Develop or Optimize a Culture Production Process for Fc-Fusion Molecules 74
• 3.3 Specific Process Considerations for Fc-Fusion Molecules 77
• 3.3.1 Product Quality Challenges 77
• 3.3.2 Process Strategies and Process Parameters 78
• 3.4 Case Studies 82
• 3.4.1 LTBr-Fc (Baminercept) 82
• 3.4.2 rFVIIIFc 85
• 3.5 Conclusions 87
• References 87
• 4 Downstream Processing of Fc-Fusion Proteins 97
• Abhinav A. Shukla and Uwe Gottschalk
• 4.1 Introduction and Overview of Fc-Fusion Proteins 97
• 4.2 Biochemistry of Fc-Fusion Proteins 99
• 4.3 Purification of Fc-Fusion Proteins from Mammalian Cells 100
• 4.3.1 Platform Approaches for Downstream Purification 100
• 4.3.2 Comparison of Protein A Chromatography, Viral Inactivation, and Polishing Steps 103
• 4.4 Purification of Fc-Fusion Protein from Microbial Systems 107
• 4.5 Future Innovations in Fc-Fusion Protein Downstream Processing 109
• 4.6 Conclusions 110
• References 111
• 5 Formulation, Drug Product, and Delivery: Considerations for Fc-Fusion Proteins 115
• Wenjin Cao, Deirdre Murphy Piedmonte, and Margaret Speed Ricci, and Ping Y. Yeh
• 5.1 Challenges of Molecule Design and Protein Formulation 115
• 5.2 The Promise of Fc-Fusion Proteins 116
• 5.3 Current Landscape of Commercial Antibody-Related Products 118
• 5.4 Fc Conjugates Compared to mAb Counterparts 118
• 5.5 Factors in Selecting Liquid versus Lyophilized Formulations 126
• 5.6 Advantages and Disadvantages of a Lyophilized Product 126
• 5.7 The General Lyophilization Formulation Strategy for Fc-Fusion Proteins 127
• 5.7.1 pH and Buffer 128
• 5.7.2 Stabilizing Agents (Cryoprotectant and Lyoprotectant) 129
• 5.8 Bulking Agent 132
• 5.9 Surfactant 134
• 5.10 The Impact of Residual Moisture 135
• 5.11 Practical Considerations for Low-Protein-Concentration Lyophilized Products 138
• 5.12 Drug Delivery Considerations 139
• 5.13 Device Considerations 141
• 5.14 Assessing Feasibility of a Multidose Formulation 142
• 5.15 Overage Considerations 142
• 5.16 Summary 143
• References 144
• 6 Quality by Design Applied to a Fc-Fusion Protein: A Case Study 155
• Alex Eon-Duval, Ralf Gleixner, Pascal Valax, Miroslav Soos, Benjamin Neunstoecklin, Massimo Morbidelli, and Herve Broly
• 6.1 Introduction 155
• 6.1.1 Atacicept: A Novel Immunomodulator with B Cell Targeting Properties 155
• 6.1.2 Molecular Characteristics 155
• 6.1.3 Quality by Design Concept 157
• 6.2 Critical Quality Attributes 159
• 6.3 Critical Process Parameters 160
• 6.4 Process Characterization 161
• 6.5 Global Multistep Design Space 164
• 6.6 Robustness Studies 168
• 6.7 Adaptive Strategy 169
• 6.8 Engineering Design Space 171
• 6.8.1 Principle of the Engineering Design Space 171
• 6.8.2 The Shear Stress as One Element of the Engineering Design Space 173
• 6.9 Control Strategy 176
• 6.9.1 Process Controls 177
• 6.9.2 Testing Controls 177
• 6.9.3 Process Monitoring 179
• 6.9.4 Material Control 179
• 6.10 Continuous Process Verification 180
• 6.11 Expanded Change Protocol and Continual Improvement 182
• 6.12 Business Case 183
• References 187
• 7 Analytical Methods Used to Characterize Fc-Fusion Proteins 191
• Esohe Idusogie and Michael Mulkerrin
• 7.1 Background 191
• 7.2 Product Characterization 193
• 7.2.1 Physiochemical Analysis 195
• 7.2.2 Measurement of Potency 201
• 7.2.3 Process-Related Impurities and Contaminants 204
• 7.3 Characterization of the Reference Standard 207
• 7.4 Typical Product Release and Stability Assays 207
• 7.5 Analytical Method Qualification and Validation 210
• References 212
• Part Two Case Studies of Therapeutic Fc-Fusion Proteins 217
• 8 Introduction to Therapeutic Fc-Fusion Proteins 219
• Jody D. Berry
• 8.1 Therapeutic Fc-Fusion Proteins 219
• 8.2 Background 221
• 8.3 Fc-Fusion Constructs Have Increased In Vivo Stability 222
• 8.4 Immunoglobulin-Mediated Effector Function 223
• 8.5 Considerations in Fc-Fusion Protein Design 226
• 8.6 Fc-Fusion Proteins Approved for Use in the United States 226
• 8.6.1 Alefacept 226
• 8.6.2 Etanercept 227
• 8.6.3 Abatacept and Belatacept 227
• 8.6.4 Aflibercept 228
• 8.6.5 rFVIIIFc and rFIXFc 228
• 8.6.6 Rilonacept 229
• 8.6.7 Romiplostim 229
• 8.6.8 Trebananib 229
• 8.7 Concluding Remarks 229
• References 230
• 9 Alefacept 233
• Deborah A. Farson
• 9.1 Introduction 233
• 9.2 Chronic Plaque Psoriasis 233
• 9.3 Conventional Treatments for Psoriasis 234
• 9.4 Preclinical Development 234
• 9.4.1 CD2/LFA-3 234
• 9.4.2 Fusion Protein Alefacept (LFA3TIP) 236
• 9.5 Preclinical Primate Studies 237
• 9.6 Phase 1 and 2 Human Clinical Studies 240
• 9.7 Phase 3 Studies 240
• 9.7.1 Study Design 242
• 9.7.2 Efficacy 245
• 9.7.3 Multiple Courses of Treatment 247
• 9.8 Clinical Pharmacology 248
• 9.9 Clinical Safety 249
• 9.9.1 Adverse Events 249
• 9.9.2 Infection 250
• 9.9.3 Cancer 250
• 9.9.4 Laboratory Tests 250
• 9.10 Amevive Discontinued 250
• References 251
• 10 Etanercept 255
• Johanna Grossman and Steven M. Chamow
• 10.1 Introduction 255
• 10.1.1 TNF Structure and Function 255
• 10.1.2 TNF Receptor Types 256
• 10.1.3 TNF Receptor Signaling 256
• 10.1.4 Role of TNF in Chronic Inflammatory Disease 259
• 10.1.5 Rheumatoid Arthritis 259
• 10.1.6 Juvenile Idiopathic Arthritis 260
• 10.1.7 Psoriatic Arthritis 260
• 10.1.8 Ankylosing Spondylitis 260
• 10.1.9 Crohn’s Disease 261
• 10.1.10 Ulcerative Colitis 261
• 10.1.11 Psoriasis 261
• 10.2 Design, Construction, and Characterization of TNFR-Fc-Fusion Protein 262
• 10.2.1 State of Therapeutic Antibodies and Rationale for a Receptor-Fc-Fusion Protein 262
• 10.3 Etanercept Preclinical Development 264
• 10.3.1 Binding and TNF Inhibitory Activity 265
• 10.3.2 Inhibition of TNF Activity 265
• 10.3.3 Preclinical Efficacy 266
• 10.3.4 Pharmacokinetics and Pharmacodynamics 266
• 10.3.5 Toxicology 267
• 10.4 Etanercept Key Clinical Trials 267
• 10.4.1 Rheumatoid Arthritis 267
• 10.4.2 Polyarticular Juvenile Idiopathic Arthritis 269
• 10.4.3 Psoriatic Arthritis 270
• 10.4.4 Ankylosing Spondylitis 270
• 10.4.5 Plaque Psoriasis 271
• 10.4.6 Other Potential Indications 272
• 10.5 Competitive Landscape 273
• 10.6 Conclusions 273
• References 274
• 11 Abatacept and Belatacept 283
• Robert J. Peach
• 11.1 Introduction 283
• 11.2 Design, Construction, and Characterization of Abatacept 285
• 11.3 Immunosuppressive Properties of Abatacept 288
• 11.4 Rational Design and Characterization of Belatacept 291
• 11.5 Belatacept Activity in Primate Renal Transplant Studies 294
• 11.6 Abatacept Clinical Development 295
• 11.7 Belatacept Clinical Development 299
• 11.8 Concluding Remarks 302
• References 303
• 12 Aflibercept 311
• Angela L. Linderholm and Steven M. Chamow
• 12.1 Introduction 311
• 12.2 Clinical Indications 311
• 12.2.1 Age-Related Macular Degeneration 311
• 12.2.2 Macular Edema with CRVO 315
• 12.2.3 Metastatic Colorectal Cancer 316
• 12.3 Characterization of Aflibercept 317
• 12.4 Preclinical Studies with Aflibercept 320
• 12.5 Clinical Studies with Aflibercept 325
• 12.5.1 Aflibercept and AMD 325
• 12.5.2 Aflibercept and Cancer 327
• 12.6 Summary 336
• References 336
• 13 Recombinant Factor VIII– and Factor IX–Fc Fusions 351
• Robert T. Peters and Judy R. Berlfein
• 13.1 Introduction 351
• 13.1.1 Treatment for Hemophilia 351
• 13.2 Structure and Function of Factor IX and Factor VIII 352
• 13.2.1 Factor IX 352
• 13.2.2 Factor VIII 354
• 13.3 Rationale and Design of rFIXFc- and rFVIIIFc-Fusion Proteins 356
• 13.3.1 Fc/FcRn Pathway for Half-Life Extension and the Monomeric Fc-Fusion 356
• 13.3.2 Beyond Science: Outside Factors for Applying Monomeric Fc Technology to Hemophilia 356
• 13.3.3 rFIXFc: Putting It Into Practice 358
• 13.3.4 rFVIIIFc: Putting It Into Practice 363
• 13.4 Development of a Clinical Candidate and Beyond 365
• 13.4.1 Preclinical and Clinical Development 365
• References 368
• Index 371

Valoración:

¡Sea el primero en dejar un comentario!

Nuevo Comentario