Aggregation of Therapeutic Proteins

by Wang, Wei; Roberts, Christopher J.

• ISBN13: 9780470411964
• ISBN10: 0470411961
• Edition: 1st
• Format: Hardcover
• Copyright: 2010-08-30
• Publisher: Wiley

Summary

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 consequences is still immature. Prevention or even moderate inhibition of protein aggregation has been mostly experimental. The knowledge in this book can greatly help pharmaceutical scientists in the development of therapeutic proteins, and also instigate further scientific investigations in this area. This book fills such a need by providing an overview on the causes, consequences, characterization, and control of the aggregation of therapeutic proteins.

Author Biography

WEI WANG, PhD, is a Research Fellow at Pfizer Global Biologics. He is also Adjunct Professor in the School of Pharmacy and Health at the University of the Pacific in California and Guest Professor at Shandong University in China.

CHRISTOPHER J. ROBERTS, PhD, is Associate Professor of Chemical Engineering at the University of Delaware. Previously, he was a senior research scientist in pharmaceutical R & D at Pfizer.

Table of Contents

Fundamental Structures and Behaviors of Proteins

The Problem of Protein Aggregation

Parallels to Protein Folding

Views of Protein Stability and Aggregation

Models of Aggregation

Models of Protein Folding

Influences of Chemical Alteration on Aggregation

Approaches to Predicting Aggregation

Conclusions

References

Protein Aggregation Pathways, Kinetics, and Thermodynamics

Introduction

Native and Non-Native Aggregation Pathway(s)

Thermodynamics of Reversible Self-Association

Aggregation Kinetics and Distinguishing Kinetic Pathways

Chemical Modifications

Effects of Cosolvents or Cosolutes

Nomenclature

Appendix - Derivation of ¿₃₂ for a van der Waals Mixture

Acknowledgements

References

Identification and Impact of Aggregation Prone Regions in Proteins and Therapeutic Monoclonal Antibodies

Introduction

Energy Landscapes, Protein Folding and Aggregation

Prediction of Aggregation Prone Regions in Proteins and Biotherapeutics

Conclusions and Future Directions

Acknowledgments

Abbreviations

References

External Factors Affecting Protein Aggregation

Introduction

Protein Aggregation Pathways

Effects of Temperature

Effects of Solution Conditions and Composition on Protein Aggregation

Effects of Processing Steps on Protein Aggregation

Effects of Solid-State Conditions and Composition on Protein Aggregation

Summary

Acknowledgements

References

Experimental Detection and Characterization of Protein Aggregates

Introduction

Aggregate Classification

Analytical Tools for Characterization of Aggregates

Summary

References

Approaches to Control Protein Aggregation during Bulk Production

Introduction

Candidate selection

Protein aggregation and cell culture

Protein aggregation and purification

Summary

References

Protein Aggregation and Particle Formation: Effects of Formulation, Interfaces and Drug Product Manufacturing Operations

Introduction

Roles of Conformational and Colloidal Stability in Reducing Rates of Aggregation

Effects of Interfaces on Protein Aggregation

Critical processing steps during drug product manufacturing of biopharmaceuticals

Particles in parenteral products and visible inspection

Summary and Outlook

References

Approaches to Managing Protein Aggregation in Product Development

Introduction

Approaches in Formulation Development

Protection of Proteins in Various Processing Steps

Aggregation Control by Structural Modifications

Summary

References

Case Studies Involving Protein Aggregation

Introduction

Case study 1. Aggregation in the liquid state: the role of osmolytes in stabilizing Keratinocyte Growth Factor (KGF) towards aggregation

Case Study 2: Aggregation in the liquid state: heterogeneity and non-linearity in IgG2 aggregation during long term storage

Case Study 3: Aggregation in the frozen state: the role of excipient crystallization

Case Studies 4&5: Aggregation in the lyophilized state: role of residual moisture and mechanisms of excipient stabilization

Case study 6: Protein particulation due to nucleation by foreign material in fill/finish manufacturing operations

Overall Discussion

Acknowledgements

References

Aggregation and Immunogenicity of Therapeutic Proteins

Introduction

Immunogenicity of therapeutic proteins

Immune mechanisms related to protein immunogenicity

Aggregates and Immunogenicity

Conclusions

References

Regulatory Perspective on Aggregates as Product Quality Attribute

Introduction

An overview of the regulatory process

Product aggregates and safety concerns

The assessment of aggregates: regulatory approaches to controlling product aggregation

Future challenges

Summary

Acknowledgements

References

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