Aggregation of Therapeutic Proteins

This book gives pharmaceutical scientists an up-to-date resource on protein aggregation and its consequences, and available methods to control or slow down the aggregation process. While significant progress has been made in the past decade, the current understanding of protein aggregation and its c...

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Bibliographic Details
Main Authors Wang, Wei, Roberts, Christopher J
Format eBook Book
LanguageEnglish
Published Hoboken, N.J Wiley 2010
John Wiley & Sons, Incorporated
Wiley-Blackwell
Edition1. Aufl.
Subjects
Aggregation (Chemistry)
Cell Aggregation
Development
Drug Discovery
MEDICAL
Pharmacology
Protein Conformation
Protein drugs
Protein Folding
Recombinant Proteins > metabolism
Recombinant Proteins > therapeutic use
Gesundheit Sonstiges
Medizin
Online AccessGet full text
ISBN0470411961
9780470411964
0470769815
9780470769812
0470769823
9780470769829
DOI10.1002/9780470769829

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Table of Contents:
  • AGGREGATION OF THERAPEUTIC PROTEINS -- CONTENTS -- PREFACE -- CONTRIBUTORS -- CHAPTER 1: Fundamental Structures and Behaviors of Proteins -- 1.1 THE PROBLEM OF PROTEIN AGGREGATION -- 1.1.1 Structural Features of Proteins -- 1.1.2 Structural Features of Protein Aggregates -- 1.2 PARALLELS TO PROTEIN FOLDING -- 1.3 VIEWS OF PROTEIN STABILITY AND AGGREGATION -- 1.3.1 Physicochemical Properties of Proteins -- 1.3.2 Surface Properties and Packing Arrangements -- 1.3.3 Solvent Interactions -- 1.4 MODELS OF AGGREGATION -- 1.4.1 Monomer Conversion -- 1.4.2 Oligomeric Intermediates -- 1.4.3 Nucleation in Protein Folding -- 1.4.4 Domain Swapping -- 1.5 MODELS OF PROTEIN FOLDING -- 1.5.1 Classical Models Based on Chemical Equilibrium -- 1.5.2 Statistical Mechanical Models -- 1.5.3 Computational Models -- 1.5.4 Application of Coarse-Grained Models -- 1.5.5 Information Theory (IT) -- 1.6 INFLUENCES OF CHEMICAL ALTERATION ON AGGREGATION -- 1.6.1 Length of the Polypeptide Chain -- 1.6.2 Methionine Oxidation -- 1.6.3 Covalent Cross-Linking of Strands -- 1.6.4 Deamidation -- 1.6.5 Proline Isomerization -- 1.7 APPROACHES TO PREDICTING AGGREGATION -- 1.8 CONCLUSIONS -- REFERENCES -- CHAPTER 2: Protein Aggregation Pathways, Kinetics, and Thermodynamics -- 2.1 INTRODUCTION -- 2.2 NATIVE AND NONNATIVE AGGREGATION PATHWAYS -- 2.3 THERMODYNAMICS OF REVERSIBLE SELF-ASSOCIATION -- 2.3.1 Self-Association of Folded/Native Proteins -- 2.3.2 Nonnative Self-Association -- 2.4 AGGREGATION KINETICS AND DISTINGUISHING KINETIC PATHWAYS -- 2.4.1 Aggregation Kinetics -- 2.4.2 Distinguishing Aggregation Pathways and Rate-Limiting Steps -- 2.4.3 Influence of Adsorption to Macroscopic Surfaces -- 2.5 CHEMICAL MODIFICATIONS -- 2.6 EFFECTS OF COSOLVENTS OR COSOLUTES -- 2.6.1 Transfer Free Energies and Preferential Interaction Parameters -- 2.6.2 Relating G32 to Molecular Interactions
  • 2.6.3 An Additive Approach to Δμ2tr, ∂μ2 ∂ 3ex m , and G32(m3) -- 2.6.4 Predicting Cosolvent/Cosolute Effects on Unfolding, Association, and Aggregation -- APPENDIX-DERIVATION OF Γ32 FOR VAN DER WAALS (vdW) MIXTURE -- ACKNOWLEDGMENTS -- REFERENCES -- CHAPTER 3: Identification and Impact of Aggregation-Prone Regions in Proteins and Therapeutic Monoclonal Antibodies -- 3.1 INTRODUCTION -- 3.2 ENERGY LANDSCAPES, PROTEIN FOLDING, AND AGGREGATION -- 3.3 PREDICTION OF APRs IN PROTEINS AND BIOTHERAPEUTICS -- 3.3.1 Computational Tools -- 3.3.2 Experimentally Studied Aggregation-Prone Sequences and Sequence Patterns -- 3.3.3 Prediction of APRs in Therapeutic mAbs -- 3.3.4 Other Useful Studies -- 3.4 CONCLUSIONS AND FUTURE DIRECTIONS -- ACKNOWLEDGMENTS -- REFERENCES -- CHAPTER 4: External Factors Affecting Protein Aggregation -- 4.1 INTRODUCTION -- 4.2 PROTEIN AGGREGATION PATHWAYS -- 4.2.1 Physical Aggregation through Formation of Unfolding Intermediates -- 4.2.2 Direct Aggregation through Self-Association or Chemical Linkages -- 4.2.3 Indirect Aggregation through Chemical Degradation -- 4.2.4 Protein Aggregation from the Unfolded State -- 4.2.5 Aggregation Nucleation -- 4.2.6 Multiplicity in Protein Aggregation -- 4.3 EFFECTS OF TEMPERATURE -- 4.3.1 Relationship between Temperature and Protein Stability -- 4.3.2 Effect of High Temperature on Protein Aggregation -- 4.3.3 Melting Temperature (Tm) and Protein Aggregation -- 4.3.4 Effects of Low Temperature -- 4.4 EFFECTS OF SOLUTION CONDITIONS AND COMPOSITION ON PROTEIN AGGREGATION -- 4.4.1 Solution pH -- 4.4.2 Type and Concentration of Buffering Agents -- 4.4.3 Ionic Strength -- 4.4.4 Excipients/Additives -- 4.4.5 Protein Concentration -- 4.4.6 Metal Ions -- 4.4.7 Denaturant and Reducing Agents -- 4.4.8 Impurities -- 4.4.9 Organic Solvents -- 4.4.10 Containers/Closures -- 4.4.11 Sources of Proteins
  • 9.5 CASE STUDIES 4 AND 5: AGGREGATION IN THE LYOPHILIZED STATE: ROLE OF RESIDUAL MOISTURE AND MECHANISMS OF EXCIPIENT STABILIZATION47,48
  • 7.5.5 Subvisible Particle Acceptance Criteria -- 7.5.6 Visual Inspection Requirements -- 7.5.7 Visual Inspection Methods -- 7.5.8 What Does "Visible" Mean? -- 7.5.9 Potential Causes of Particulate Contamination in Parenteral Products -- 7.6 SUMMARY AND OUTLOOK -- REFERENCES -- CHAPTER 8: Approaches to Managing Protein Aggregation in Product Development -- 8.1 INTRODUCTION -- 8.2 APPROACHES IN FORMULATION DEVELOPMENT -- 8.2.1 Traditional Formulation Development -- 8.2.2 High-Throughput Formulation Development (HTFD) -- 8.2.3 Computer-Assisted Design of Formulations -- 8.3 PROTECTION OF PROTEINS IN VARIOUS PROCESSING STEPS -- 8.3.1 Shaking -- 8.3.2 Freezing/Thawing -- 8.3.3 Manufacturing Processes for Liquid Drug Product -- 8.3.4 Drying -- 8.3.5 Reconstitution -- 8.3.6 Preparation of Controlled Protein Delivery Systems -- 8.3.7 Miscellaneous Processes -- 8.4 AGGREGATION CONTROL BY STRUCTURAL MODIFICATIONS -- 8.4.1 Mutagenesis -- 8.4.2 PEG ylation -- 8.4.3 Glycosylation -- 8.5 SUMMARY -- REFERENCES -- CHAPTER 9: Case Studies Involving Protein Aggregation -- 9.1 INTRODUCTION -- 9.2 CASE STUDY 1: AGGREGATION IN THE LIQUID STATE: THE ROLE OF OSMOLYTES IN STABILIZING KGF TOWARD AGGREGATION -- 9.2.1 Background -- 9.2.2 Model Protein and Conditions -- 9.2.3 Results and Interpretation -- 9.2.4 Discussion and Lessons Learned -- 9.3 CASE STUDY 2: AGGREGATION IN THE LIQUID STATE: HETEROGENEITY AND NON-LINEARITY IN IgG2 AGGREGATION DURING LONG-TERM STORAGE35 -- 9.3.1 Background -- 9.3.2 Model Protein and Conditions -- 9.3.3 Results and Interpretation -- 9.3.4 Discussion and Lessons Learned -- 9.4 CASE STUDY 3: AGGREGATION IN THE FROZEN STATE: THE ROLE OF EXCIPIENT CRYSTALLIZATION42 -- 9.4.1 Background -- 9.4.2 Model Protein and Conditions -- 9.4.3 Results and Interpretation -- 9.4.4 Discussion and Lessons Learned
  • 4.4.12 Light -- 4.5 EFFECTS OF PROCESSING STEPS ON PROTEIN AGGREGATION -- 4.5.1 Fermentation/Expression -- 4.5.2 Unfolding/Refolding -- 4.5.3 Purification -- 4.5.4 Freeze-Thaw -- 4.5.5 Agitation -- 4.5.6 High Hydrostatic Pressure -- 4.5.7 Drying -- 4.5.8 Preparation of Protein Delivery Systems -- 4.5.9 Analytical Methodologies -- 4.5.10 Miscellaneous Processes -- 4.6 EFFECTS OF SOLID-STATE CONDITION AND COMPOSITION ON PROTEIN AGGREGATION -- 4.6.1 Solid-State "pH" -- 4.6.2 Excipients and Excipient Levels -- 4.6.3 Physical State of the Solid -- 4.6.4 Moisture Content -- 4.7 SUMMARY -- ACKNOWLEDGMENT -- REFERENCES -- CHAPTER 5: Experimental Detection and Characterization of Protein Aggregates -- 5.1 INTRODUCTION -- 5.2 AGGREGATE CLASSIFICATION -- 5.2.1 Aggregate Nomenclature -- 5.3 ANALYTICAL TOOLS FOR THE CHARACTERIZATION OF AGGREGATES -- 5.3.1 SEC -- 5.3.2 Light Scattering -- 5.3.3 Analytical Ultracentrifugation (AUC) -- 5.3.4 FFF -- 5.3.5 Electrophoresis -- 5.3.6 Turbidimetry and Nephelometry -- 5.3.7 Analytical Techniques for Subvisible Particles -- 5.3.8 Visible Particles -- 5.3.9 Miscellaneous Technologies for Characterization of Protein Aggregates -- 5.3.10 Protein Structural Characterization in Aggregates: Spectroscopy-Based Techniques -- 5.4 SUMMARY -- REFERENCES -- CHAPTER 6: Approaches to Control Protein Aggregation during Bulk Production -- 6.1 INTRODUCTION -- 6.2 CANDIDATE SELECTION -- 6.2.1 Sequence Analysis -- 6.2.2 Stability to Process Conditions -- 6.2.3 Focus on Stability to Formulation and Long-Term Storage Conditions -- 6.2.4 Specific Considerations for Mammalian Cell Culture-Derived Protein -- 6.2.5 Specific Considerations for Bacteria-Derived Protein -- 6.3 PROTEIN AGGREGATION AND CELL CULTURE -- 6.3.1 Expression Strategies -- 6.3.2 Bioreactor Conditions -- 6.4 PROTEIN AGGREGATION AND PURIFICATION
  • 6.4.1 Preventing Aggregation with Appropriate Solvent Conditions -- 6.4.2 Removal of Aggregates during Processing -- 6.4.3 Specific Considerations for Mammalian Cell-Derived Protein -- 6.4.4 Specific Considerations for Bacterial-Derived Proteins -- 6.4.5 Bulk DS Stability and Storage -- 6.4.6 Scale-Up -- 6.5 SUMMARY -- REFERENCES -- CHAPTER 7: Protein Aggregation and Particle Formation: Effects of Formulation, Interfaces, and Drug Product Manufacturing Operations -- 7.1 INTRODUCTION -- 7.2 ROLES OF CONFORMATIONAL AND COLLOIDAL STABILITY IN REDUCING RATES OF AGGREGATION -- 7.2.1 Conformational Stability -- 7.2.2 Colloidal Stability -- 7.3 EFFECTS OF INTERFACES ON PROTEIN AGGREGATION -- 7.3.1 Effects of Air-Water Interface -- 7.3.2 Protein Aggregation at Solid-Liquid Interfaces -- 7.3.3 Effects of Excipients on Structural Perturbation and Aggregation at Surfaces -- 7.3.4 Interactions of Proteins with Microparticle Surfaces -- 7.3.5 Protein Aggregation at Silicone Oil/Water Interfaces -- 7.3.6 Shear Effects on Protein Aggregation -- 7.4 CRITICAL PROCESSING STEPS DURING DRUG PRODUCT MANUFACTURING OF BIOPHARMACEUTICALS -- 7.4.1 Freezing and Thawing Operations -- 7.4.2 Mixing of Bulk Drug Solution after Thawing or Pooling -- 7.4.3 Preparation of Final Formulation with Excipients -- 7.4.4 Filtration -- 7.4.5 Filling -- 7.5 PARTICLES IN PARENTERAL PRODUCTS AND VISIBLE INSPECTION -- 7.5.1 Introduction: Understanding of Particles from the Parenteral Product Viewpoint is Important for Protein Biopharmaceutical Developers -- 7.5.2 The History of Visible Inspection and Particle Contamination Control in Parenteral Products -- 7.5.3 Current Regulatory Requirements on Particulate Contamination and Control of Subvisible and Visible Particles in Parenteral Products in the EU, United States, and Japan -- 7.5.4 Subvisible Particle Measurements