Protein Analysis using Mass Spectrometry
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List of Contributors xiii
Foreword xvii
Preface xix
1 Contemporary Protein Analysis by Ion Mobility Mass Spectrometry 1
Johannes 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 11
Hongxia 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 21
Zhiqi 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 35
Suma 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 45
Shane 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 55
Jiang 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 67
Bradley 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 91
Jianing 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 99
Xuejiang 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) 107
Brian 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 129
Stanley (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 145
Hongyan 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 161
Michael 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 183
Yongjun 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 203
Long 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 221
Wei 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
