Targeted Biomarker Quantitation by LC-MS

Naidong Weng, PhD, is Scientific Director, Janssen Fellow, and Head of Bioanalytical Chemistry and Pharmacokinetics within Department of Pharmacokinetics, Dynamics and Metabolism at US East Coast, Janssen Research & Development, Johnson and Johnson. He has over 25 years of experiences on quantitative bioanalysis. His research interest includes using HILIC-MS/MS for quantitation of highly polar analytes as well as chiral analysis. He has published more than 110 journal papers and book chapters. Wenying Jian, PhD, a Senior Principal Scientist of Bioanalytical Chemistry and Pharmacokinetics within Department of Pharmacokinetics, Dynamics and Metabolism at US East Coast, Janssen Research & Development, Johnson and Johnson. Her research experience and interest center on application of advanced LC-MS methodologies in detection, identification, and quantitation of endogenous molecules, drugs and their metabolites, including small and large molecules, and in complicated biological matrices. She has published more than 40 journal papers and book chapters.

• List of Contributors xvPreface xixAbbreviations xxiiiPart I Overview 11 Overview of Targeted Quantitation of Biomarkers and Its Applications 3Naidong Weng1.1 Introduction 31.2 Biomarker Definition 41.3 Current Challenges of a Biomarker 51.4 Biomarker Validation Process 61.5 Current Regulatory Requirement for Target Biomarker Quantitation 61.6 Challenges of Biomarker Quantitation 71.7 Current Technologies for Biomarker Quantitation 81.8 Current Biomarker Quantitation Applications 91.9 Conclusion and Future Perspective 12References 132 Translational Application of Biomarkers 17Ray Bakhtiar2.1 Introduction 172.2 Translational Medicine 172.3 Biomarkers 182.4 Biomarker Categories 182.5 Neurobiological Disorders 212.6 Cardiovascular Disorders 222.7 Chronic Obstructive Pulmonary Disease 232.8 Oncology 242.9 Biomarker Measurements and Regulatory Considerations 262.10 Conclusions 27References 293 Current Regulatory Guidance Pertaining Biomarker Assay Establishment and Industrial Practice of Fit‐for‐Purpose and Tiered Approach 35Naidong Weng3.1 Introduction 353.2 Current Regulatory Guidance and Interpretation 363.3 Current Industrial Discussion and Recommendations 373.4 Considerations for Assay Validation and Sample Analysis 393.5 Examples of Fit‐for‐Purpose and Tiered Approach 413.6 Conclusion 42References 424 Modern Liquid Chromatography and Mass Spectrometry for Targeted Biomarker Quantitation 45Wenying Jian4.1 Introduction 454.2 Liquid Chromatography 454.3 Mass Spectrometry 514.4 Summary and Future Perspectives 58References 595 Comparison Between LC–MS and Ligand‐Binding Assay Approaches for Biomarker Quantification 65QingQing Wang, Lili Guo, and Ian A. Blair5.1 General Considerations: LBAs or LC–MS Assays 655.2 General Quantification Approaches 665.3 Analytical Issues Specifically Related to LBAs 675.4 Analytical Features Specifically Related to LC–MS Methods 685.5 Case Studies: Comparison Between ELISA and LC–MS 725.6 Summary and Future Perspective 74References 746 Sample Preparation Methods for Targeted Biomarker Quantification by LC‐MS 79Shichen Shen, Bo An, and Jun Qu6.1 Introduction 796.2 Sample Preparation Strategies for Small Molecule Biomarkers 796.3 Sample Preparation Strategies for Macromolecule Biomarkers 866.4 Conclusive Remarks 94References 957 Overcome the Endogenous Levels in Biomarker Quantitation Using LC–MS 107Guowen Liu7.1 Introduction 1077.2 How Does Matrix Effect Affect Quantitation? 1087.3 Commonly Used Strategies 1097.4 Discussions and Future Perspectives 114References 115Part II Challenges and Approaches 1198 Sample Collection for Targeted Biomarker Quantitation by LC–MS 121Yuzhong Deng and Xiaorong Liang8.1 Introduction 1218.2 Timing of Biomarker Sample Collection 1218.3 Matrix Type 1228.4 Collection Methods 1248.5 Sample Storage Stability 1288.6 Summary 129References 1309 Nonspecific Binding in LC–MS Bioanalysis 137Aimin Tan and John C. Fanaras9.1 Introduction 1379.2 Identification and Evaluation of NSB 1379.3 Causes for NSB 1409.4 Overcoming NSB Challenges 1409.5 Conclusion 144References 14610 Strategies for Improving Sensitivity for Targeted Quantitation by LC–MS 149Long Yuan and Qin C. Ji10.1 Introduction 14910.2 Sample Preparation Strategies for Improving Sensitivity 15010.3 LC Separation Strategies for Improving Sensitivity 15610.4 MS Detection Strategies for Improving Sensitivity 16010.5 Conclusions 163References 16311 Strategies to Improve Specificity for Targeted Biomarker Quantitation by LC–MS 171Yuan‐Qing Xia and Jeffrey D. Miller11.1 Introduction 17111.2 Differential Mobility Spectrometry 17111.3 High‐Resolution Mass Spectrometry 17511.4 Conclusions 180References 18012 Biomarker Quantitation Using Relative Approaches 183Shane M. Lamos and Katrina E. Wiesner12.1 Introduction 18312.2 Relative Quantitation Isotope Labeling Approaches 18312.3 Conclusions 191References 192Part III Applications 19513 Targeted Quantification of Amino Acid Biomarkers Using LC‐MS 197Barry R. Jones, Raymond F. Biondolillo, and John E. Buckholz13.1 Introduction 19713.2 Amino Acids as Biomarkers 19813.3 Methods of Measurement 20113.4 Accuracy, Precision, Selectivity, and Stability Considerations 20313.5 Assay Design 20713.6 Conclusion 207References 20814 Targeted Quantification of Peptide Biomarkers: A Case Study of Amyloid Peptides 211Lieve Dillen, Marc De Meulder, and Tom Verhaeghe14.1 Overview 21114.2 Challenges and Approaches 21214.3 Application to the Quantification of Alzheimer’s Disease Biomarkers 21614.4 Conclusion 222References 22215 Targeted Protein Biomarker Quantitation by LC‐MS 227Yongle Pang, Chuan Shi, and Wenying Jian15.1 Introduction 22715.2 Sample Preparation for Targeted Protein Biomarker Quantitation 23115.3 “Bottom‐Up” Approach for Targeted Protein Biomarker Quantitation Using LC‐MS 23315.4 “Top Down” Approach for Targeted Protein Biomarker Quantitation Using LC‐MS 23515.5 Key Considerations in Targeted Protein Biomarker Quantitation Using LC‐MS 23615.6 Summary and Future Perspectives 239References 24016 Glycoprotein Biomarkers 245Shuwei Li, Stefani N. Thomas, and Shuang Yang16.1 Introduction 24516.2 Technologies for Glycoprotein Analysis 24616.3 Glycoprotein Biomarker Quantification Using LC‐MS 25516.4 Protein Biomarkers for Clinical Applications 25916.5 Summary and Future Direction 264References 26517 Targeted Lipid Biomarker Quantitation Using Liquid Chromatography–Mass Spectrometry (LC–MS) 273Ashkan Salamatipour, Ian A. Blair, and Clementina Mesaros17.1 Introduction of Lipids 27317.2 LC–MS Analysis of Lipids 27617.3 Examples of LC–MS Analysis of Lipids 27817.4 Summary and Future Directions 283References 28318 Targeted LC–MS Quantification of Androgens and Estrogens for Biomarker Development 289Daniel Tamae18.1 Introduction 28918.2 Current Considerations in Biomarker Validation 29218.3 Current Considerations in LC–MS Method Development 29318.4 Clinical Application of LC–MS Quantification of Estrogens and Androgens 29618.5 Conclusion and Perspective 301References 30119 Steroid Biomarkers 307Mike (Qingtao) Huang, Shefali Patel, and Zhongping (John) Lin19.1 Introduction 30719.2 Sterols as Endogenous Biomarkers and Their Quantitation 30719.3 Cortisol and 6 β‐Hydroxycortisol (6β‐HC) as Biomarkers and Their Quantitation 31219.4 Summary 316References 31620 Bile Acids as Biomarkers 321Clara John, Philipp Werner, Joerg Heeren, and Markus Fischer20.1 Introduction 32120.2 Analytical Platform for Bile Acids 32320.3 Summary 327References 32721 Biomarkers for Vitamin Status and Deficiency: LC‐MS Based Approach 331Stanley (Weihua) Zhang and Jonathan Crowther21.1 Introduction to Vitamin and Vitamin Deficiency 33121.2 Detection of Vitamin D by LC‐MS/MS and Comparison with Other Methods 33221.3 Other Vitamin Biomarkers 33821.4 Conclusions and Perspectives 340References 34122 Quantitation of Acyl‐Coenzyme A Thioesters as Metabolic Biomarkers 347Nathaniel Snyder22.1 Introduction 34722.2 Structure and Function of Acyl‐CoAs 34722.3 Detection and Quantitation of Acyl‐CoAs 34922.4 Acyl‐CoA Analysis for Current Drug Targets 35222.5 Acyl‐CoAs as Biomarkers in Metabolic Disease 35222.6 The Involvement of Acyl‐CoAs in Drug Metabolism 353References 35323 Neurotransmitter Biomarkers 357Guodong Zhang23.1 Introduction 35723.2 Chromatographic Platforms of Biological Measurement for Neurotransmitters 35823.3 Bioanalytical Methodologies 35923.4 Conclusion 367References 36724 Targeted Quantification of Carbohydrate Biomarkers Using LC–MS 371Cong Wei and Hong Gao24.1 Introduction 37124.2 Overview 37124.3 Bioanalytical Method Development for Carbohydrate Biomarkers 37424.4 Conclusions 384References 38425 Nucleoside/Nucleotide Biomarkers 389Guodong Zhang25.1 Introduction 38925.2 Chromatographic Platforms for Nucleosides/Nucleotides 39025.3 Bioanalytical Methodologies 39125.4 Nucleoside/Nucleotide Biomarkers and Case Studies 39825.5 Conclusion 399References 40226 LC–MS of RNA Biomarkers 407Michael G. Bartlett, Babak Basiri, and Ning li26.1 Introduction 40726.2 Role in Disease and Therapeutics 40826.3 Role of Mass Spectrometry in RNA Biomarkers 40926.4 LC–MS Approaches for RNA Determination 41126.5 Case Studies 415References 418Index 425