Antibody-Drug Conjugates (eBook, ePUB)

Fundamentals, Drug Development, and Clinical Outcomes to Target Cancer
Redaktion: Olivier, Kenneth J.; Hurvitz, Sara A.

• Format: ePub

Produktbeschreibung

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

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Produktdetails

• Verlag: John Wiley & Sons
• Seitenzahl: 560
• Erscheinungstermin: 14. November 2016
• Englisch
• ISBN-13: 9781119060802
• Artikelnr.: 47138907

Autorenporträt

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.

Inhaltsangabe

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
töAntibody 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
töAntibody 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 AdöTrastuzumab 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