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Protein Analysis using Mass Spectrometry. Accelerating Protein Biotherapeutics from Lab to Patient. Wiley Series on Pharmaceutical Science and Biotechnology: Practices, Applications and Methods

  • ID: 3993873
  • Book
  • 288 Pages
  • John Wiley and Sons Ltd
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Presents Practical Applications of Mass Spectrometry for Protein Analysis and Covers Their Impact on Accelerating Drug Discovery and Development

Protein biotherapeutics has become a large portion of drug candidates and newly developed drugs aimed at conquering unmet medical needs. In recent years protein biotherapeutics have become an essential part of medical treatments for cancers and autoimmune diseases. Protein Analysis using Mass Spectrometry: Accelerating Protein Biotherapeutics from Lab to Patient describes the practical applications of mass spectrometry for protein analysis as well as their impact on accelerating drug discovery and development.

Analytical sciences used to develop technologies and methodologies to probe unknown systems quantitatively and qualitatively are one of essential components for delivering effective protein biotherapeutics. As protein molecules continue to be linked to diseases there is an increased opportunity for developing protein biotherapeutics to treat these diseases. The book brings together the most current advances in mass spectrometry technologies and related methods in order to accomplish this.

Doctors and nurses, lab managers, lab technicians, and pharmaceutical researches from academia and industry as well as researchers and developers will find this reference a useful tool in their research.

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List of Contributors xiii

Foreword xvii

Preface xix

1 Contemporary Protein Analysis by Ion Mobility Mass Spectrometry 1Johannes P.C. Vissers and James I. Langridge

1.1 Introduction 1

1.2 Traveling–Wave Ion Mobility Mass Spectrometry 1

1.3 IM MS and LC IM MS Analysis of Simple and Complex Mixtures 2

1.4 Outlook 7

Acknowledgment 8

References 8

2 High–Resolution Accurate Mass Orbitrap and Its Application in Protein Therapeutics Bioanalysis 11Hongxia Wang and Patrick Bennett

2.1 Introduction 11

2.2 Triple Quadrupole Mass Spectrometer and Its Challenges 11

2.3 High–Resolution Mass Spectrometers 12

2.4 Quantitation Modes on Q Exactive Hybrid Quadrupole Orbitrap 13

2.5 Protein Quantitation Approaches Using Q Exactive Hybrid Quadrupole Orbitrap 14

2.6 Data Processing 16

2.7 Other Factors That Impact LC MS–based Quantitation 16

2.8 Conclusion and Perspectives of LC HRMS in Regulated Bioanalysis 18

References 18

3 Current Methods for the Characterization of Posttranslational Modifications in Therapeutic Proteins Using Orbitrap Mass Spectrometry 21Zhiqi Hao, Qiuting Hong, Fan Zhang, Shiaw–Lin Wu, and Patrick Bennett

3.1 Introduction 21

3.2 Characterization of PTMs Using Higher–Energy Collision Dissociation 23

3.3 Application of Electron Transfer Dissociation to the Characterization of Labile PTMs 26

3.4 Conclusion 31

Acknowledgment 32

References 32

4 Macro– to Micromolecular Quantitation of Proteins and Peptides by Mass Spectrometry 35Suma Ramagiri, Brigitte Simons, and Laura Baker

4.1 Introduction 35

4.2 Key Challenges of Peptide Bioanalysis 36

4.3 Key Features of LC/MS/MS–Based Peptide Quantitation 38

4.4 Advantages of the Diversity of Mass Spectrometry Systems 41

4.5 Perspectives for the Future 41

References 42

5 Peptide and Protein Bioanalysis Using Integrated Column–to–Source Technology for High–Flow Nanospray 45Shane R. Needham and Gary A. Valaskovic

5.1 Introduction LC MS Has Enabled the Field of Protein Biomarker Discovery 45

5.2 Integration of Miniaturized LC with Nanospray ESI–MS Is a Key for Success 46

5.3 Micro– and Nano–LC Are Well Suited for Quantitative Bioanalysis 47

5.4 Demonstrating Packed–Emitter Columns Are Suitable for Bioanalysis 49

5.5 Future Outlook 51

References 52

6 Targeting the Right Protein Isoform: Mass Spectrometry–Based Proteomic Characterization of Alternative Splice Variants 55Jiang Wu

6.1 Introduction 55

6.2 Alternative Splicing and Human Diseases 55

6.3 Identification of Splice Variant Proteins 56

6.4 Conclusion 64

References 64

7 The Application of Immunoaffinity–Based Mass Spectrometry to Characterize Protein Biomarkers and Biotherapeutics 67Bradley L. Ackermann and Michael J. Berna

7.1 Introduction 67

7.2 Overview of IA–MS Methods 69

7.3 IA–MS Applications Biomarkers 74

7.3.1 Peptide Biomarkers 74

7.4 IA–MS Applications Biotherapeutics 81

7.5 Future Direction 84

References 85

8 Semiquantification and Isotyping of Antidrug Antibodies by Immunocapture–LC/MS for Immunogenicity Assessment 91Jianing Zeng, Hao Jiang, and Linlin Luo

8.1 Introduction 91

8.2 Multiplexing Direct Measurement of ADAs by Immunocapture–LC/MS for Immunogenicity Screening, Titering, and Isotyping 93

8.3 Indirect Measurement of ADAs by Quantifying ADA Binding Components 95

8.4 Use of LC MS to Assist in Method Development of Cell–Based Neutralizing Antibody Assays 96

8.5 Conclusion and Future Perspectives 97

References 97

9 Mass Spectrometry–Based Assay for High–Throughput and High–Sensitivity Biomarker Verification 99Xuejiang Guo and Keqi Tang

9.1 Background 99

9.2 Sample Processing Strategies 100

9.3 Advanced Electrospray Ionization Mass Spectrometry Instrumentation 102

9.4 Conclusion 105

References 105

10 Monitoring Quality of Critical Reagents Used in Ligand Binding Assays with Liquid Chromatography Mass Spectrometry (LC MS) 107Brian Geist, Adrienne Clements–Egan, and Tong–Yuan Yang

10.1 Introduction 107

10.2 Case Study Examples 114

10.3 Discussion 122

Acknowledgment 126

References 126

11 Application of Liquid Chromatography–High Resolution Mass Spectrometry in the Quantification of Intact Proteins in Biological Fluids 129Stanley (Weihua) Zhang, Jonathan Crowther, and Wenying Jian

11.1 Introduction 129

11.2 Workflows for Quantification of Proteins Using Full–Scan LC–HRMS 131

11.3 Internal Standard Strategy 133

11.4 Calibration and Quality Control (QC) Sample Strategy 135

11.5 Common Issues in Quantification of Proteins Using LC–HRMS 135

11.6 Examples of LC–HRMS–Based Intact Protein Quantification 137

11.7 Conclusion and Future Perspectives 138

Acknowledgment 140

References 140

12 LC MS/MS Bioanalytical Method Development Strategy for Therapeutic Monoclonal Antibodies in Preclinical Studies 145Hongyan Li, Timothy Heath, and Christopher A. James

12.1 Introduction: LC–MS/MS Bioanalysis of Therapeutic Monoclonal Antibodies 145

12.2 Highlights of Recent Method Development Strategies 146

12.3 Case Studies of Preclinical Applications of LC MS/MS for Monoclonal Antibody Bioanalysis 154

12.4 Conclusion and Future Perspectives 156

References 158

13 Generic Peptide Strategies for LC MS/MS Bioanalysis of Human Monoclonal Antibody Drugs and Drug Candidates 161Michael T. Furlong

13.1 Introduction 161

13.2 A Universal Peptide LC MS/MS Assay for Bioanalysis of a Diversity of Human Monoclonal Antibodies and Fc Fusion Proteins in Animal Studies 161

13.3 An Improved Dual Universal Peptide LC MS/MS Assay for Bioanalysis of Human mAb Drug Candidates in Animal Studies 165

13.4 Extending the Universal Peptide Assay Concept to Human mAb Bioanalysis in Human Studies 170

13.5 Internal Standard Options for Generic Peptide LC MS/MS Assays 173

13.6 Sample Preparation Strategies for Generic Peptide LC MS/MS Assays 175

13.7 Limitations of Generic Peptide LC MS/MS Assays 177

13.8 Conclusion 178

Acknowledgments 178

References 178

14 Mass Spectrometry–Based Methodologies for Pharmacokinetic Characterization of Antibody Drug Conjugate Candidates During Drug Development 183Yongjun Xue, Priya Sriraman, Matthew V. Myers, Xiaomin Wang, Jian Chen, Brian Melo, Martha Vallejo, Stephen E. Maxwell, and Sekhar Surapaneni

14.1 Introduction 183

14.2 Mechanism of Action 183

14.3 Mass Spectrometry Measurement for DAR Distribution of Circulating ADCs 186

14.4 Total Antibody Quantitation by Ligand Binding or LC MS/MS 189

14.5 Total Conjugated Drug Quantitation by Ligand Binding or LC MS/MS 193

14.6 Catabolite Quantitation by LC MS/MS 196

14.7 Preclinical and Clinical Pharmacokinetic Support 197

14.8 Conclusion and Future Perspectives 198

References 198

15 Sample Preparation Strategies for LC MS Bioanalysis of Proteins 203Long Yuan and Qin C. Ji

15.1 Introduction 203

15.2 Sample Preparation Strategies to Improve Assay Sensitivity 205

15.3 Sample Preparation Strategies to Differentiate Free, Total, and ADA–Bound Proteins 213

15.4 Sample Preparation Strategies to Overcome Interference from Antidrug Antibodies or Soluble Target 214

15.5 Protein Digestion Strategies 214

15.6. Conclusion 215

Acknowledgment 216

References 216

16 Characterization of Protein Therapeutics by Mass Spectrometry 221Wei Wu, Hangtian Song, Thomas Slaney, Richard Ludwig, Li Tao, and Tapan Das

16.1 Introduction 221

16.2 Variants Associated with Cysteine/Disulfide Bonds in Protein Therapeutics 221

16.3 N C–Terminal Variants 225

16.4 Glycation 226

16.5 Oxidation 226

16.6 Discoloration 228

16.7 Sequence Variants 230

16.8 Glycosylation 232

16.9 Conclusion 240

References 240

Index 251

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Mike S. Lee
Qin C. Ji
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