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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