Cover Title Page Copyright Contents List of Contributors Preface Historical Perspective: What Makes Antibody-Drug Conjugates Revolutionary? Introduction Early Work in Monoclonal Antibody Development: Ehrlich's Magic Bullets Use of Monoclonal Antibodies to Identify and Treat Cancer Linking Monoclonal Antibodies with Cytotoxic Agents Antibody-Drug Conjugates in the Clinic Why ADCs Are Revolutionary? References Part I 1 What is an Antibody-Drug Conjugate Chapter 1 Typical Antibody-Drug Conjugates 1.1 Introduction 1.1.1 A Simple Concept 1.1.2 Turning Antibodies into Potent Anticancer Compounds 1.1.3 What is a Typical ADC and How Does it Act? 1.1.4 Simple Concept, but Not So Simple to Execute 1.2 The Building Blocks of a Typical ADC 1.2.1 The Antibody 220.127.116.11 Antibody Isotype in ADCs 18.104.22.168 Functional Activity of the Antibody Moiety in ADCs 1.2.2 The Payload 22.214.171.124 DNA-Targeting Payloads 126.96.36.199 Payloads Targeting Tubulin 1.2.3 Linker Chemistries 1.3 Building an ADC Molecule 1.3.1 Conjugation of Payloads to Antibodies at Lysine Residues 1.3.2 Conjugation of Payloads to Antibodies at Cysteine Residues 1.4 Attributes of a Typical ADC 1.4.1 Structural Attributes of a Typical ADC 1.4.2 Functional Characteristics of a Typical ADC 188.8.131.52 In Vitro Properties 184.108.40.206 In Vivo Efficacy 220.127.116.11 Pharmacokinetics of ADCs 1.5 Summary Acknowledgment References Part II Engineering, Manufacturing, and Optimizing Antibody-Drug Conjugates Chapter 2 Selecting Optimal Antibody-Drug Conjugate Targets Using Indication-Dependent or Indication-Independent Approaches 2.1 Characteristics of an Optimal ADC Target 2.2 Indication-Dependent ADC Target Selection 2.3 Indication-Independent ADC Target Selection. 2.4 Concluding Remarks and Future Directions Acknowledgments References Chapter 3 Antibody-Drug Conjugates: An Overview of the CMC and Characterization Process 3.1 Introduction 3.2 ADC Manufacturing Process 3.2.1 Conjugation 3.2.2 Conjugation - Next‐Generation Chemistry 18.104.22.168 Conjugation - Novel Payloads 22.214.171.124 Conjugation - Linker Design 3.2.3 mAb Engineering 3.2.4 Purification 3.2.5 Formulation 3.3 Characterization 3.3.1 Quality and Stability Testing 3.3.2 Biochemical and Microbiological Testing 3.3.3 Extended Characterization 3.4 Comparability 3.5 Concluding Remarks References Chapter 4 Linker and Conjugation Technology and Improvements 4.1 Overview 4.2 Noncleavable 4.3 Cleavable Linkers and Self-Immolative Groups 4.4 Differences in Therapeutic Window of Cleavable and Noncleavable Linkers 4.5 Improving Therapeutic Window with Next-Generation Linker Technologies 4.6 Site-Specific Conjugation, Homogeneous Drug Species, and Therapeutic Window 4.7 Influence of Linkers on Pharmacokinetics and ADME 4.8 PEG Linkers to Optimize Clearance, Solubility, and Potency 4.9 Linkers to Optimize for Drug Resistance 4.10 Improving Solid Tumor Penetration with Linkers 4.11 Analytical Methods for Characterizing Linker Pharmacodynamics 4.12 Conclusion References Chapter 5 Formulation and Stability 5.1 Introduction 5.2 Stability Considerations for ADCs 5.2.1 Physical Stability 5.2.2 Chemical Stability 5.3 Formulation Approaches 5.4 Logistical Considerations 5.5 Summary and Close References Chapter 6 QC Assay Development 6.1 Introduction 6.2 Drug-to-Antibody Ratio 6.3 Drug Loading Distribution 6.3.1 Lysine‐Linked ADCs 6.3.2 Cysteine‐Linked ADCs 6.4 Positional Isomers 6.5 ADC Concentration. 6.6 Drug-Related Substances 6.7 Antigen Binding Assays and Potential Impact of Drug Conjugation 6.8 Cell-Based Cytotoxicity Assays 6.9 Assays to Monitor Fc-Dependent Effector Functions to Characterize Additional Possible Mechanisms of Action 6.10 Immunogenicity Assays to Monitor the Immune Response to ADC 6.11 Conclusions 6.12 Key Guidance Documents Acknowledgments References Chapter 7 Occupational Health and Safety Aspects of ADCs and Their Toxic Payloads 7.1 Introduction 7.2 Background on ADCs 7.2.1 Payloads 7.2.2 Linker Technologies 7.2.3 Antibodies 7.2.4 Partial Conjugates 7.3 Occupational Hazard Assessment of ADCs and Their Components 7.4 Occupational Implications and Uncertainties 7.4.1 Routes of Occupational Exposure 7.4.2 Binding Efficiency (Payload to Antibody) 7.4.3 Unintended Targets 7.4.4 Free Payload in Conjugation Formulation 7.4.5 Local Effects in the Lung 7.5 General Guidance for Material Handling 7.5.1 Handling of Powders 7.5.2 Handling of Solutions 7.6 Facility Features and Engineering Controls 7.6.1 HVAC and Air Pressure Relationships 7.6.2 Air Changes and Airflow 7.6.3 Recirculation and Filtration of Room Air 7.6.4 Changing Areas 7.6.5 Designated Areas 7.7 Specific Operational Guidance 7.7.1 Payload Synthesis 7.7.2 Conjugation 7.7.3 Lyophilization 7.7.4 Cleaning 7.8 Personal Protective Equipment 7.8.1 Chemical Protective Clothing 126.96.36.199 Protective Clothing 188.8.131.52 Gloves 184.108.40.206 Eye and Face Protection 7.8.2 Respiratory Protection 7.9 Training 7.9.1 Potent Compound Awareness Training 7.9.2 Standard Operating Procedures for Synthesizing and Handling ADCs 7.10 Industrial Hygiene Monitoring 7.10.1 Air Monitoring 7.10.2 Surface Monitoring 7.11 Medical Surveillance Program. 7.12 Summary and Future Direction References Part III Nonclinical Approaches Chapter 8 Bioanalytical Strategies Enabling Successful ADC Translation 8.1 Introduction 8.2 ADC LC/MS Bioanalytical Strategies 8.2.1 Nonregulated Unconjugated Payload Bioanalysis 8.2.2 Intact Protein Bioanalysis by LC/MS: Measurement of Drug‐to‐Antibody Ratio 8.2.3 ADC Pharmacokinetic Bioanalysis by LC/MS 8.2.4 Calculated Conjugated Payload Determination 8.2.5 Conjugated Payload Quantitation of Cleavable Linker ADCs 8.2.6 Conjugated Payload Quantitation by Peptide‐Based Analysis 8.3 Non-Regulated ADC Pharmacokinetic and Immunogenicity Support Using Ligand Binding Assays 8.3.1 ADC Ligand Binding Assays 8.3.2 Reagents 8.3.3 ADC Reference Standards 8.3.4 Total Antibody Assays 8.3.5 ADC Assays 8.3.6 Target Interference in ADC Measurement 8.3.7 ADC Immunogenicity Assays 8.4 Biodistribution Assessment 8.5 Regulated ADC Pharmacokinetics and Immunogenicity Evaluation 8.5.1 ADC Assays in Regulated Studies 8.5.2 Regulated Ligand Binding Assays 8.5.3 Regulated LC/MS/MS Quantitation of Unconjugated Payload 8.5.4 Regulated Conjugated Payload LC/MS Assays 8.5.5 Regulated Anti‐therapeutic Assays 8.6 ADC Biomeasures and Biomarkers 8.7 Summary References Chapter 9 Nonclinical Pharmacology and Mechanistic Modeling of Antibody-Drug Conjugates in Support of Human Clinical Trials 9.1 Introduction 9.2 Cell Line Testing 9.2.1 Antigen Density 9.2.2 Antigen and Antibody-Drug Conjugate Internalization 9.2.3 Payload Processing and Binding 9.3 Xenograft Models 9.3.1 Payload Bystander Effects 9.3.2 Biomarker Assays 9.4 Nonclinical Testing to Support Investigational New Drug Applications 9.4.1 Antibody-Drug Conjugate Efficacious Dose Range. 9.5 Mechanistic Modeling of Antibody-Drug Conjugates 9.5.1 Tumor Tissue Transport Considerations 9.5.2 Subcellular Trafficking 9.5.3 Shed Antigen and Endosomal Processing 9.5.4 Enhanced Pharmacokinetic Modeling to Enable Antibody-Drug Conjugate Pharmacology Predictions 9.5.5 Mechanistic Modeling of Antibody-Drug Conjugate Pharmacology: Accounting for Uncertainties 9.6 Target-Mediated Toxicity of Antibody-Drug Conjugates 9.7 Considerations for Nonclinical Testing Beyond Antibody-Drug Conjugate Monotherapies 9.8 Summary Acknowledgments References Chapter 10 Pharmacokinetics of Antibody-Drug Conjugates 10.1 Introduction 10.2 Pharmacokinetic Characteristics of an ADC 10.2.1 ADC Biodistribution 10.2.2 ADC Clearance 10.3 Unique Considerations for ADC Pharmacokinetics 10.3.1 Linker Stability 10.3.2 Site of Conjugation and Drug Load 10.3.3 Cytotoxic Drug 10.4 Tools to Characterize ADC PK/ADME 10.4.1 Bioanalytical Methods 10.4.2 In Vitro Assays 10.4.3 In Vivo Studies 10.4.4 Pharmacokinetic/Pharmacodynamic (PK/PD) Models 10.5 Utilization of ADC Pharmacokinetics to Optimize Design 10.6 Pharmacokinetics of Selected ADCs 10.6.1 Ado‐Trastuzumab Emtansine (Kadcyla®) 10.6.2 Brentuximab Vedotin (Adcetris®) 10.7 Summary References Chapter 11 Path to Market Approval: Regulatory Perspective of ADC Nonclinical Safety Assessments 11.1 Introduction 11.2 FDA Experience with ADCs 11.3 Regulatory Perspective of the Nonclinical Safety Assessment of ADCs 11.3.1 Regulatory Guidance Available for Nonclinical Studies 220.127.116.11 Species Selection 18.104.22.168 Study Duration and Dose Regimen 22.214.171.124 Study Test Article 126.96.36.199 Pharmacology Studies 188.8.131.52 Pharmacokinetics/Toxicokinetics 184.108.40.206 Genotoxicity 220.127.116.11 Developmental and Reproductive Toxicology. 18.104.22.168 First-in-Human Dose Selection.
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Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, 2021. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries.