Antibody-Drug Conjugates Fundamentals, Drug Development, and Clinical Outcomes to Target Cancer
, by Olivier, Kenneth J.; Hurvitz, Sara A.
- ISBN: 9781119060680 | 1119060680
- Cover: Hardcover
- Copyright: 11/14/2016
Providing practical and proven solutions for antibody-drug conjugate (ADC) drug discovery success in oncology, this book helps readers improve the drug safety and therapeutic efficacy of ADCs to kill targeted tumor cells.
• Discusses the basics, drug delivery strategies, pharmacology and toxicology, and regulatory approval strategies
• Covers the conduct and design of oncology clinical trials and the use of ADCs for tumor imaging
• Includes case studies of ADCs in oncology drug development
• Features contributions from highly-regarded experts on the frontlines of ADC research and development
Kenneth J. Olivier, Jr., PhD, is Head of Toxicology, Discovery Regulatory, Bioanalytical Assay Development, Pharmacokinetics and Discovery Project Management at Merrimack Pharmaceuticals and has over 13 years’ experience in the biotechnology and pharmaceutical industries.
Sara A. Hurvitz, MD, is an Associate Professor of Medicine at the University of California, Los Angeles (UCLA); Co-Director of the Santa Monica-UCLA Outpatient Oncology Practice; Medical Director of the Clinical Research Unit of the Jonsson Comprehensive Cancer Center of UCLA; and Director of the Breast Oncology Program, Division of Hematology-Oncology, at UCLA.
Sara A. Hurvitz, MD, is an Associate Professor of Medicine at the University of California, Los Angeles (UCLA); Co-Director of the Santa Monica-UCLA Outpatient Oncology Practice; Medical Director of the Clinical Research Unit of the Jonsson Comprehensive Cancer Center of UCLA; and Director of the Breast Oncology Program, Division of Hematology-Oncology, at UCLA.
List of Contributors xvii
Preface xxi
Historical Perspective: What Makes Antibody–Drug Conjugates Revolutionary? xxiii
Part I What is an Antibody–Drug Conjugate 1
1 Typical Antibody–Drug Conjugates 3
John M. Lambert
1.1 Introduction 3
1.2 The Building Blocks of a Typical ADC 6
1.3 Building an ADC Molecule 13
1.4 Attributes of a Typical ADC 19
1.5 Summary 24
Acknowledgment 24
Abbreviations 25
References 25
Part II Engineering, Manufacturing, and Optimizing Antibody–Drug Conjugates 33
2 Selecting Optimal Antibody–Drug Conjugate Targets Using Indication-Dependent or Indication-Independent Approaches 35
Jay Harper and Robert Hollingsworth
2.1 Characteristics of an Optimal ADC Target 35
2.2 Indication-Dependent ADC Target Selection 40
2.3 Indication-Independent ADC Target Selection 48
2.4 Concluding Remarks and Future Directions 50
Acknowledgments 52
References 52
3 Antibody–Drug Conjugates: An Overview of the CMC and Characterization Process 59
Philip L. Ross and Janet Wolfe
3.1 Introduction 59
3.2 ADC Manufacturing Process 60
3.3 Characterization 70
3.4 Comparability 76
3.5 Concluding Remarks 76
Abbreviations 77
References 78
4 Linker and Conjugation Technology; and Improvements 85
Riley Ennis and Sourav Sinha
4.1 Overview 85
4.2 Noncleavable 86
4.3 Cleavable Linkers and Self-Immolative Groups 86
4.4 Differences in Therapeutic Window of Cleavable and Noncleavable Linkers 88
4.5 Improving Therapeutic Window with Next-Generation Linker Technologies 89
4.6 Site-Specific Conjugation, Homogeneous Drug Species, and Therapeutic Window 91
4.7 Influence of Linkers on Pharmacokinetics and ADME 93
4.8 PEG Linkers to Optimize Clearance, Solubility, and Potency 93
4.9 Linkers to Optimize for Drug Resistance 94
4.10 Improving Solid Tumor Penetration with Linkers 96
4.11 Analytical Methods for Characterizing Linker Pharmacodynamics 96
4.12 Conclusion 98
References 99
5 Formulation and Stability 105
Kouhei Tsumoto, Anthony Young, and Satoshi Ohtake
5.1 Introduction 105
5.2 Stability Considerations for ADCs 106
5.3 Formulation Approaches 115
5.4 Logistical Considerations 123
5.5 Summary and Close 125
References 126
6 QC Assay Development 131
Xiao Hong. Chen and Mate Tolnay
6.1 Introduction 131
6.2 Drug-to-Antibody Ratio 132
6.3 Drug Loading Distribution 133
6.4 Positional Isomers 136
6.5 ADC Concentration 136
6.6 Drug-Related Substances 137
6.7 Antigen Binding Assays and Potential Impact of Drug Conjugation 137
6.8 Cell-Based Cytotoxicity Assays 139
6.9 Assays to Monitor Fc-Dependent Effector Functions to Characterize Additional Possible Mechanisms of Action 140
6.10 Immunogenicity Assays to Monitor the Immune Response to ADC 142
6.11 Conclusions 144
6.12 Key Guidance Documents 145
Acknowledgments 145
References 145
7 Occupational Health and Safety Aspects of ADCs and Their Toxic Payloads 151
Robert Sussman and John Farris
7.1 Introduction 151
7.2 Background on ADCs 152
7.3 Occupational Hazard Assessment of ADCs and Their Components 157
7.4 Occupational Implications and Uncertainties 159
7.5 General Guidance for Material Handling 160
7.6 Facility Features and Engineering Controls 163
7.7 Specific Operational Guidance 165
7.8 Personal Protective Equipment 167
7.9 Training 168
7.10 Industrial Hygiene Monitoring 169
7.11 Medical Surveillance Program 171
7.12 Summary and Future Direction 172
References 172
Part III Nonclinical Approaches 177
8 Bioanalytical Strategies Enabling Successful ADC Translation 179
Xiaogang Han, Steven Hansel, and Lindsay King
8.1 Introduction 179
8.2 ADC LC/MS Bioanalytical Strategies 182
8.3 Non-Regulated ADC Pharmacokinetic and Immunogenicity Support Using Ligand Binding Assays 190
8.4 Biodistribution Assessment 195
8.5 Regulated ADC Pharmacokinetics and Immunogenicity Evaluation 196
8.6 ADC Biomeasures and Biomarkers 199
8.7 Summary 200
References 201
9 Nonclinical Pharmacology and Mechanistic Modeling of Antibody–Drug Conjugates in Support of Human Clinical Trials 207
Brian J. Schmidt, Chin Pan, Heather E. Vezina, Huadong Sun, Douglas D. Leipold, and Manish Gupta
9.1 Introduction 207
9.2 Cell Line Testing 210
9.3 Xenograft Models 214
9.4 Nonclinical Testing to Support Investigational New Drug Applications 216
9.5 Mechanistic Modeling of Antibody–Drug Conjugates 220
9.6 Target-Mediated Toxicity of Antibody–Drug Conjugates 228
9.7 Considerations for Nonclinical Testing Beyond Antibody–Drug Conjugate Monotherapies 229
9.8 Summary 230
Acknowledgments 231
References 231
10 Pharmacokinetics of Antibody–Drug Conjugates 245
Amrita V. Kamath
10.1 Introduction 245
10.2 Pharmacokinetic Characteristics of an ADC 246
10.3 Unique Considerations for ADC Pharmacokinetics 250
10.4 Tools to Characterize ADC PK/ADME 254
10.5 Utilization of ADC Pharmacokinetics to Optimize Design 257
10.6 Pharmacokinetics of Selected ADCs 259
10.7 Summary 261
References 262
11 Path to Market Approval: Regulatory Perspective of ADC Nonclinical Safety Assessments 267
M. Stacey Ricci, R. Angelo De Claro, and Natalie E. Simpson
11.1 Introduction 267
11.2 FDA Experience with ADCs 268
11.3 Regulatory Perspective of the Nonclinical Safety Assessment of ADCs 269
11.4 Concluding Remarks 282
References 283
Part IV Clinical Development and Current Status of Antibody–Drug Conjugates 285
12 Antibody–Drug Conjugates: Clinical Strategies and Applications 287
Heather E. Vezina, Lucy Lee, Brian J. Schmidt, and Manish Gupta
12.1 Antibody–Drug Conjugates in Clinical Development 287
12.2 Therapeutic Indications 291
12.3 Transitioning from Discovery to Early Clinical Development 292
12.4 Challenges and Considerations in the Design of Phase 1 Studies 293
12.5 First-in-Human Starting Dose Estimation 293
12.6 Dosing Strategy Considerations 294
12.7 Dosing Regimen Optimization 295
12.8 Phase 1 Study Design 297
12.9 Supportive Strategies for Phase 1 and Beyond 299
12.10 Clinical Pharmacology Considerations 301
12.11 Organ Impairment Assessments 301
12.12 Drug–Drug Interaction Assessments 302
12.13 Immunogenicity 303
12.14 QT/QTc Assessments 303
12.15 Pharmacometric Strategies 307
12.16 Using Physiologically Based Pharmacokinetic and Quantitative Systems Pharmacology Models with Clinical Data 308
12.17 Summary and Conclusions 311
Acknowledgments 311
References 311
13 Antibody–Drug Conjugates (ADCs) in Clinical Development 321
Joseph McLaughlin and Patricia LoRusso
13.1 Introduction and Rationale 321
13.2 Components of ADCs in Development 321
13.3 Landscape of ADCs 329
13.4 Clinical Use of ADCs 330
13.5 Future of ADCs 330
13.6 ADCs in Development 330
13.7 Future Directions 340
References 340
14 ADCs Approved for Use: Trastuzumab Emtansine (Kadcyla®, T-DM1) in Patients with Previously Treated HER2-Positive Metastatic Breast Cancer 345
Gail D. Lewis Phillips, Sanne de Haas, Sandhya Girish, and Ellie Guardino
14.1 Introduction 345
14.2 Preclinical Development of T-DM1 348
14.3 Early Clinical Studies of T-DM1 357
14.4 Clinical Pharmacology and Pharmacokinetics 361
14.5 Phase III Studies of T-DM1 in Patients with HER2-Positive MBC 362
14.6 Future Directions 371
14.7 Summary 373
References 374
15 ADCs Approved for Use: Brentuximab Vedotin 381
Monica Mead and Sven de Vos
15.1 Introduction 381
15.2 Early Efforts to Target CD30 with Monoclonal Antibodies 383
15.3 BV: Preclinical Data 386
15.4 Clinical Context 394
15.5 Mechanisms of Resistance 395
15.6 Current Research 397
15.7 Discussion 400
References 401
16 Radioimmunotherapy 409
Savita V. Dandapani and Jeffrey Wong
16.1 History of Radioimmunotherapy 409
16.2 Radioisotopes 410
16.3 Chemistry of RIT 411
16.4 Radioimmunotherapy Antibody Targets in Use Today (Table 16.2) 412
16.5. Other Hematologic Targets 415
16.6 Solid Tumors 417
16.7 Combination Therapy with RIT: Chemotherapy and/or Radiation 420
16.8 RIT and External Beam Radiation Treatment (EBRT) 421
16.9 RIT and EBRT and Chemotherapy 421
16.10 RIT Administration 422
16.11 Future of RIT 422
References 423
Part V Future Perspectives in Antibody–Drug Conjugate Development 431
17 Radiolabeled Antibody-Based Imaging in Clinical Oncology 433
Bart S. Hendriks and Daniel F. Gaddy
17.1 Introduction 433
17.2 Applications for Clinical Antibody Imaging 434
17.3 Antibodies as Imaging Agents 435
17.4 Nuclear Imaging – Gamma Camera (Planar) Scintigraphy and SPECT 439
17.5 Nuclear Imaging - PET 448
17.6 Commercialization Considerations 456
17.7 Summary 461
References 462
18 Next-Generation Antibody–Drug Conjugate Technologies 473
Amy Q. Han and William C. Olson
18.1 Introduction 473
18.2 Novel Cytotoxic Payloads and Linkers 474
18.3 Tailoring Antibodies for Use as ADCs 482
18.4 Conclusions 491
References 491
Index 505
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