Antibody-Drug Conjugates - Fundamentals, Drug Development, and Clinical Outcomes to Target Cancer

פרטים

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

מידע נוסף

מידע נוסף
עמודים	560
פורמט	Hardback
ISBN10	1119060680
יצא לאור ב	Hoboken
תאריך יציאה לאור	20 בדצמ׳ 2016
תוכן עניינים	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(R), 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
זמן אספקה	21 ימי עסקים