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Antibody-Drug Conjugates -

Antibody-Drug Conjugates

Fundamentals, Drug Development, and Clinical Outcomes to Target Cancer
Buch | Hardcover
560 Seiten
2016
John Wiley & Sons Inc (Verlag)
978-1-119-06068-0 (ISBN)
CHF 219,95 inkl. MwSt
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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.

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

1.1.1 A Simple Concept 3

1.1.2 Turning Antibodies into Potent Anticancer Compounds 4

1.1.3 What is a Typical ADC and How Does it Act? 4

1.1.4 Simple Concept, but Not So Simple to Execute 5

1.2 The Building Blocks of a Typical ADC 6

1.2.1 The Antibody 6

1.2.1.1 Antibody Isotype in ADCs 7

1.2.1.2 Functional Activity of the Antibody Moiety in ADCs 8

1.2.2 The Payload 9

1.2.2.1 DNA-Targeting Payloads 11

1.2.2.2 Payloads Targeting Tubulin 11

1.2.3 Linker Chemistries 12

1.3 Building an ADC Molecule 13

1.3.1 Conjugation of Payloads to Antibodies at Lysine Residues 13

1.3.2 Conjugation of Payloads to Antibodies at Cysteine Residues 17

1.4 Attributes of a Typical ADC 19

1.4.1 Structural Attributes of a Typical ADC 19

1.4.2 Functional Characteristics of a Typical ADC 20

1.4.2.1 In Vitro Properties 20

1.4.2.2 In Vivo Efficacy 20

1.4.2.3 Pharmacokinetics of ADCs 23

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

3.2.1 Conjugation 62

3.2.2 Conjugation – Next‐Generation Chemistry 64

3.2.2.1 Conjugation – Novel Payloads 64

3.2.2.2 Conjugation – Linker Design 65

3.2.3 mAb Engineering 66

3.2.4 Purification 68

3.2.5 Formulation 68

3.3 Characterization 70

3.3.1 Quality and Stability Testing 70

3.3.2 Biochemical and Microbiological Testing 74

3.3.3 Extended Characterization 74

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

5.2.1 Physical Stability 106

5.2.2 Chemical Stability 111

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

6.3.1 Lysine‐Linked ADCs 134

6.3.2 Cysteine‐Linked ADCs 134

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

7.2.1 Payloads 153

7.2.2 Linker Technologies 154

7.2.3 Antibodies 156

7.2.4 Partial Conjugates 156

7.3 Occupational Hazard Assessment of ADCs and Their Components 157

7.4 Occupational Implications and Uncertainties 159

7.4.1 Routes of Occupational Exposure 159

7.4.2 Binding Efficiency (Payload to Antibody) 159

7.4.3 Unintended Targets 160

7.4.4 Free Payload in Conjugation Formulation 160

7.4.5 Local Effects in the Lung 160

7.5 General Guidance for Material Handling 160

7.5.1 Handling of Powders 162

7.5.2 Handling of Solutions 162

7.6 Facility Features and Engineering Controls 163

7.6.1 HVAC and Air Pressure Relationships 164

7.6.2 Air Changes and Airflow 164

7.6.3 Recirculation and Filtration of Room Air 164

7.6.4 Changing Areas 164

7.6.5 Designated Areas 165

7.7 Specific Operational Guidance 165

7.7.1 Payload Synthesis 165

7.7.2 Conjugation 166

7.7.3 Lyophilization 166

7.7.4 Cleaning 167

7.8 Personal Protective Equipment 167

7.8.1 Chemical Protective Clothing 167

7.8.1.1 Protective Clothing 167

7.8.1.2 Gloves 167

7.8.1.3 Eye and Face Protection 168

7.8.2 Respiratory Protection 168

7.9 Training 168

7.9.1 Potent Compound Awareness Training 169

7.9.2 Standard Operating Procedures for Synthesizing and Handling ADCs 169

7.10 Industrial Hygiene Monitoring 169

7.10.1 Air Monitoring 170

7.10.2 Surface Monitoring 170

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

8.2.1 Nonregulated Unconjugated Payload Bioanalysis 183

8.2.2 Intact Protein Bioanalysis by LC/MS: Measurement of Drug‐to‐Antibody Ratio 184

8.2.3 ADC Pharmacokinetic Bioanalysis by LC/MS 186

8.2.4 Calculated Conjugated Payload Determination 187

8.2.5 Conjugated Payload Quantitation of Cleavable Linker ADCs 188

8.2.6 Conjugated Payload Quantitation by Peptide‐Based Analysis 189

8.3 Non‐Regulated ADC Pharmacokinetic and Immunogenicity Support Using Ligand Binding Assays 190

8.3.1 ADC Ligand Binding Assays 190

8.3.2 Reagents 191

8.3.3 ADC Reference Standards 192

8.3.4 Total Antibody Assays 192

8.3.5 ADC Assays 193

8.3.6 Target Interference in ADC Measurement 194

8.3.7 ADC Immunogenicity Assays 194

8.4 Biodistribution Assessment 195

8.5 Regulated ADC Pharmacokinetics and Immunogenicity Evaluation 196

8.5.1 ADC Assays in Regulated Studies 196

8.5.2 Regulated Ligand Binding Assays 197

8.5.3 Regulated LC/MS/MS Quantitation of Unconjugated Payload 198

8.5.4 Regulated Conjugated Payload LC/MS Assays 199

8.5.5 Regulated Anti‐therapeutic Assays 199

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

9.2.1 Antigen Density 211

9.2.2 Antigen and Antibody–Drug Conjugate Internalization 211

9.2.3 Payload Processing and Binding 213

9.3 Xenograft Models 214

9.3.1 Payload Bystander Effects 215

9.3.2 Biomarker Assays 216

9.4 Nonclinical Testing to Support Investigational New Drug Applications 216

9.4.1 Antibody–Drug Conjugate Efficacious Dose Range 218

9.5 Mechanistic Modeling of Antibody–Drug Conjugates 220

9.5.1 Tumor Tissue Transport Considerations 221

9.5.2 Subcellular Trafficking 225

9.5.3 Shed Antigen and Endosomal Processing 225

9.5.4 Enhanced Pharmacokinetic Modeling to Enable Antibody–Drug Conjugate Pharmacology Predictions 226

9.5.5 Mechanistic Modeling of Antibody–Drug Conjugate Pharmacology: Accounting for Uncertainties 227

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

10.2.1 ADC Biodistribution 248

10.2.2 ADC Clearance 249

10.3 Unique Considerations for ADC Pharmacokinetics 250

10.3.1 Linker Stability 250

10.3.2 Site of Conjugation and Drug Load 252

10.3.3 Cytotoxic Drug 253

10.4 Tools to Characterize ADC PK/ADME 254

10.4.1 Bioanalytical Methods 254

10.4.2 In Vitro Assays 255

10.4.3 In Vivo Studies 256

10.4.4 Pharmacokinetic/Pharmacodynamic (PK/PD) Models 256

10.5 Utilization of ADC Pharmacokinetics to Optimize Design 257

10.6 Pharmacokinetics of Selected ADCs 259

10.6.1 Ado‐Trastuzumab Emtansine (Kadcyla®) 259

10.6.2 Brentuximab Vedotin (Adcetris®) 261

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

11.3.1 Regulatory Guidance Available for Nonclinical Studies 270

11.3.1.1 Species Selection 272

11.3.1.2 Study Duration and Dose Regimen 275

11.3.1.3 Study Test Article 276

11.3.1.4 Pharmacology Studies 278

11.3.1.5 Pharmacokinetics/Toxicokinetics 279

11.3.1.6 Genotoxicity 280

11.3.1.7 Developmental and Reproductive Toxicology 280

11.3.1.8 First-in-Human Dose Selection 280

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

13.2.1 Antibody 321

13.2.2 Linker 327

13.2.3 Payload 328

13.3 Landscape of ADCs 329

13.3.1 History of ADCs 329

13.3.2 FDA Approved ADCs 329

13.4 Clinical Use of ADCs 330

13.5 Future of ADCs 330

13.6 ADCs in Development 330

13.6.1 Hematological Malignancies and Renal Cell Carcinoma 330

13.6.1.1 Auristatins (MMAE and MMAF) 330

13.6.1.2 Maytansinoids (DM1 and DM4) 332

13.6.1.3 Pyrrolobenzodiazepines (PBDs) 334

13.6.1.4 Calicheamicins 335

13.6.1.5 Others 335

13.6.2 Solid Malignancies 335

13.6.2.1 Auristatins (MMAE and MMAF) 335

13.6.2.2 Maytansinoids (DM1 and DM4) 338

13.6.2.3 Others 339

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-DM 1 348

14.3 Early Clinical Studies of T-DM 1 357

14.3.1 Phase I Adverse Events (AEs) 357

14.3.2 Phase I Efficacy 358

14.3.3 Dosing Schedule 359

14.3.4 Phase II Trials 359

14.4 Clinical Pharmacology and Pharmacokinetics 361

14.5 Phase III Studies of T-DM1 in Patients with HER2-Positive MBC 362

14.5.1 EMILIA Trial 363

14.5.2 TH3RESA Trial 367

14.5.3 Treatment Exposure 369

14.5.4 Biomarkers as Predictors of Efficacy 369

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

15.3.1 Clinical Data: Safety/Tolerability 388

15.3.2 Clinical Data: Efficacy 391

15.3.3 CD30 Expression Level and Response to BV 393

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

16.4.1 Hematologic Malignancies 412

16.4.1.1 CD20 412

16.5. Other Hematologic Targets 415

16.5.1 Lymphomas 415

16.5.1.1 Lym-1, CD22, CD 25 415

16.5.2 Leukemias 417

16.5.2.1 CD33 417

16.6 Solid Tumors 417

16.6.1 CEA (Carcinoembryonic Antigen) 418

16.6.2 Other RIT in Solid Tumors 419

16.7 Combination Therapy with RIT: Chemotherapy and/or Radiation 420

16.7.1 RIT and Chemotherapy 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

17.4.1 Tumor Detection and Staging 440

17.4.1.1 CEA 441

17.4.1.2 PSMA 441

17.4.1.3 TAG‐72 443

17.4.1.4 Pancarcinoma Antigen 443

17.4.2 Diagnostic Assessment 444

17.4.2.1 HER2 444

17.4.2.2 EGFR 445

17.4.3 Dosimetry for Radioimmunotherapy 445

17.4.4 Early Assessment of Response 447

17.5 Nuclear Imaging ‐ PET 448

17.5.1 68Ga 448

17.5.2 64Cu 449

17.5.3 89Zr 451

17.5.4 124I 454

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

18.2.1 Microtubule Inhibitors 474

18.2.2 Benzodiazepine Dimers 474

18.2.3 Anthracyclines 477

18.2.4 Amatoxins 478

18.2.5 Disulfide Rebridging 479

18.2.6 FleximerTM Polymeric Linkers 481

18.3 Tailoring Antibodies for Use as ADCs 482

18.3.1 Engineered Cysteines 483

18.3.2 Enzyme-Assisted Conjugation 484

18.3.2.1 Microbial Transglutaminase 484

18.3.2.2 Formylglycine-Generating Enzyme (FGE) 485

18.3.2.3 Glucosyltransferases and Other Glycan Engineering 486

18.3.3 Non-Native Amino Acids and Selenocysteine 487

18.3.4 Alternative Formats and Masked Antibodies 488

18.3.5 ADCs Beyond Oncology 489

18.4 Conclusions 491

References 491

Index 505

Erscheinungsdatum
Verlagsort New York
Sprache englisch
Maße 165 x 236 mm
Gewicht 885 g
Themenwelt Medizin / Pharmazie Medizinische Fachgebiete Onkologie
Naturwissenschaften Biologie
Naturwissenschaften Chemie
Technik
ISBN-10 1-119-06068-0 / 1119060680
ISBN-13 978-1-119-06068-0 / 9781119060680
Zustand Neuware
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