ADME and Translational Pharmacokinetics / Pharmacodynamics of Therapeutic Proteins

Honghui Zhou is a Senior Director and Janssen Fellow, at Janssen Research & Development, LLC and US head of Pharmacological and Translational Modeling. Board-certified by the American Board of Clinical Pharmacology and a Fellow of American Association of Pharmaceutical Scientists (AAPS) and American College of Clinical Pharmacology (ACCP), he has authored 200 peer-reviewed scientific papers, book chapters, and conference abstracts and co-edited the book Drug-Drug Interactions for Therapeutic Biologics (Wiley, 2013).Frank-Peter Theil heads nonclinical development at UCB Biopharma. Dr. Theil has authored and co-authored 40 research publications, three book chapters and he has given numerous invited presentations at national and international scientific meetings. He is a member of the American Association of Pharmaceutical Scientists (AAPS) and American Society of Clinical Pharmacology and Therapeutics (ASCPT).

• List of Contributors xviiForeword xix1 ADME for Therapeutic Biologics: What Can We Leverage from Great Wealth of ADME Knowledge and Research for Small Molecules 1Weirong Wang and Thomayant Prueksaritanont1.1 Introduction 11.2 SM Drug Discovery and Development: Historical Perspective 11.2.1 Evolving Role of DMPK: Paradigm Shift 11.2.2 Key Enablers to Successful DMPK Support 21.2.3 Regulatory Considerations 31.3 LM Drug Discovery and Development 31.3.1 Role of DMPK: Current State 31.3.2 SM/LM DMPK Analogy 41.3.3 Leveraging SM Experience: Case Examples 61.4 Conclusions 8References 82 Protein Engineering: Applications to Therapeutic Proteins and Antibodies 13Andrew G. Popplewell2.1 Introduction 132.2 Methods of Protein Engineering 132.2.1 General Techniques 132.2.2 Introducing Specific, Directed Sequence Changes 142.2.3 Fragment Fusion 142.2.4 Gene Synthesis 142.2.5 Molecular “Evolution” through Display and Selection 142.3 Applications of Protein Engineering to Non-Antibody Therapeutic Proteins 162.4 Applications of Protein Engineering to Therapeutic Antibodies 162.4.1 Reduction of Immunogenicity 172.4.2 Improving Stability and Biophysical Properties 172.4.3 Tailoring Mechanism of Action 192.4.4 Influencing Distribution and PK 192.4.5 Improving Ligand/Receptor Interaction 202.5 Future Perspectives 20References 213 Therapeutic Antibodies—Protein Engineering to Influence ADME, PK, and Efficacy 25Tatsuhiko Tachibana, Kenta Haraya, Yuki Iwayanagi and Tomoyuki Igawa3.1 Introduction 253.2 Relationship between pI and Pharmacokinetics 263.2.1 pI and Clearance 263.2.2 pI and Distribution 263.2.3 pI and SC Absorption 273.2.4 pI and FcRn Function 273.3 Nonspecific/Specific Off‐Target Binding 273.3.1 Nonspecific Binding and Clearance 273.3.2 Specific Off‐Target Binding and Clearance 283.4 pH‐Dependent Antigen Binding to Reduce Target‐Mediated Elimination 283.4.1 Concept of Recycling Antibody 283.4.2 pH Dependency and Target‐Mediated Elimination 293.5 Soluble Antigen Sweeping 313.5.1 Concept of Sweeping Antibody 313.5.2 FcRn‐Mediated Sweeping 313.5.3 FcγRIIb‐Mediated Sweeping 333.6 Future Perspectives 34References 344 ADME for Therapeutic Biologics: Antibody‐Derived Proteins and Proteins with Novel Scaffolds 39Chetan Rathi and Bernd Meibohm4.1 Introduction 394.2 Antibody–Drug Conjugates 394.2.1 Components of ADCs 404.2.2 Types of ADC Analytes and Their PK Interpretation 414.2.3 PK of ADC 424.2.4 Immunogenicity of ADC 454.2.5 Exposure–Response of ADCs 454.2.6 Dose‐Dependent PK of ADCs 454.3 Bispecifics 454.3.1 Bispecific Antibody Formats 464.3.2 PK of Bispecific Constructs 474.3.3 Immunogenicity of Bispecific Constructs 484.3.4 Examples of Bispecific Therapeutics—Oncology Indications 484.3.5 Examples of Bispecific Therapeutics—CNS Indications 494.3.6 Examples of Bispecific Therapeutics—Ocular Indications 494.4 Conclusions 50References 505 Overview of ADME and PK/PD of ADCs 55Baiteng Zhao and Tae H. Han5.1 Introduction to ADC 555.2 Absorption 565.3 Distribution 585.4 Metabolism/Catabolism 585.5 Drug‐Linker Stability 595.6 Elimination 605.7 Clinical PK 605.8 PK and PK/PD Modeling for ADCs 615.9 Summary 62References 636 Role of Lymphatic System in Subcutaneous Absorption of Therapeutic Proteins 67Jiunn H. Lin and Weirong Wang6.1 Introduction 676.2 Physiology of Subcutaneous Tissue 686.3 Interstitial Transport from SC Injection Site 686.4 Relative Role of Blood and Lymphatic Systems in SC Absorption 696.5 Presystemic Catabolism in SC Absorption of Proteins 726.6 Effect of Injection Site on SC Absorption 746.7 Conclusions 74References 757 Biodistribution of Therapeutic Biologics: Methods and Applications in Informing Target Biology, Pharmacokinetics, and Dosing Strategies 77Sean B. Joseph, Saileta Prabhu and C. Andrew Boswell7.1 Introduction 777.2 Determinants of Antibody Biodistribution 777.2.1 Molecular Properties 787.2.2 Physiological (Tissue) Properties 797.3 Methods of Measuring Antibody Biodistribution 817.3.1 In Vivo Study Design Considerations 817.3.2 Tissue Analysis 857.4 Interpretation of Biodistribution Data 857.4.1 Calculations and Units 867.4.2 Compartmental Tissue Concentrations 867.4.3 Blood Correction 867.4.4 Derivation of Interstitial Concentrations 877.4.5 Confirmation of Receptor Occupancy 877.4.6 Explaining Unexpectedly Rapid Clearance 877.4.7 Assisting in Clinical Dose Selection 877.5 Concluding Remarks 87Acknowledgments 88References 888 Prediction of Human Pharmacokinetics for Protein‐Based Biologic Therapeutics 91Chao Han and Christina Lourdes Mayer8.1 Introduction 918.2 General Allometric Scaling and Interspecies Scaling Methods 928.3 Considerations for Interspecies Scaling of Protein‐Based Biologic Therapeutics 938.3.1 Considerations for Interspecies Scaling of mAbs 958.3.2 Other Factors that may Affect PK Interspecies Scaling for Protein‐Based Therapeutics 988.4 Physiologically Based PK Modeling 1008.5 Perspectives Beyond the Prediction 1018.5.1 Prediction of Human PK Serves Different Purposes at Different Stages of Drug Development 1018.5.2 Safety Considerations When Predicting Human PK for Protein‐Based Therapeutics 1028.6 Conclusions 102References 1029 Fixed Dosing versus Body‐Size‐Based Dosing for Therapeutic Biologics—A Clinical Pharmacology Strategy 107Diane D. Wang, Justin T. Hoffman and Kourosh Parivar9.1 Introduction 1079.1.1 Considerations for the Selection of a Dosing Approach 1089.1.2 Evaluations of Fixed Dosing versus Body‐Size‐Based Dosing 1109.1.3 Rationale Dosing Approach Selection Strategies Based on Stage of Clinical Development 1219.2 Conclusions 122References 12210 Impact of Diseases, Comorbidity, and Target Physiology on ADME, PK, and PK/PD of Therapeutic Biologics 125Songmao Zheng, Weirong Wang and Honghui Zhou10.1 Introduction 12510.1.1 ADME of Biologics 12510.1.2 Roles of TMDD for Biologics 12610.2 Impact of Diseases and Comorbidity on ADME and PK of Therapeutic Biologics 12610.2.1 Disease and Comorbidity on the Subcutaneous Absorption of Biologics 12610.2.2 Disease and Comorbidity on the Distribution of Biologics 12710.2.3 Hepatic Impairment 12810.2.4 Renal Impairment 12810.2.5 Immune‐Mediated Inflammatory Diseases 12910.2.6 Diabetes 12910.2.7 Immunogenicity 13010.3 Impact of Disease and Target Physiology on PK and PK/PD of Therapeutic Biologics 13010.3.1 Biologics against Membrane‐Bound Targets 13010.3.2 Biologics against Soluble Targets 13310.3.3 When Targets Exist as Both Membrane‐Bound and Soluble 13310.4 Correlation between the PK of Therapeutic Biologics and Treatment Response 13410.5 Other Patient Characteristics that can Impact the Treatment Response of Therapeutic Biologics 13510.6 The Interplay between Disease, Target Physiology, and PK/PD of Therapeutic Biologics: Case Examples 13610.7 Concluding Remarks 138Acknowledgments 138References 13811 Immunogenicity: Its Impact on ADME of Therapeutic Biologics 147Harald Kropshofer and Wolfgang F. Richter11.1 Introduction 14711.2 Immunogenicity of Therapeutic Biologics 14711.2.1 The Underlying Cellular Immunology 14711.2.2 Aspects Facilitating Immune Responses against Biologics 14911.3 Impact of ADA on ADME 15011.3.1 Impact of ADA on Bioanalytical Results 15011.3.2 Formation of Immune Complexes 15011.3.3 Clearance of Immune Complexes 15111.3.4 Sustaining and Clearing ADAs 15311.3.5 Impact of ADAs on Distribution 15511.3.6 Impact of ADAs on Absorption 15511.4 How to Deal with ADME Consequences of Immune Responses? 15511.4.1 PK Assessment in the Presence of ADAs 15511.4.2 In‐Study Options to Overcome ADA Formation 15611.5 Summary and Conclusions 156References 15712 Mechanistic Physiologically Based Pharmacokinetic Models in Development of Therapeutic Monoclonal Antibodies 159Yanguang Cao and William J. Jusko12.1 Background 15912.2 History 15912.3 Principles and Methods       16212.4 Challenges 16512.4.1 Physiological Parameters 16512.4.2 Extravasation Mechanisms 16512.4.3 FcRn Function 16512.5 Simplified PBPK Models for mAbs 16612.5.1 Minimal PBPK Models 16612.5.2 Survey of mAb PK in Humans with the Minimal PBPK Model 16812.5.3 Minimal PBPK Model with Target‐Mediated Drug Disposition 16912.6 Perspectives 171Acknowledgments 172References 17213 Integrated Quantitation of Biotherapeutic Drug–Target Binding, Biomarkers, and Clinical Response to Support Rational Dose Regimen Selection 175Philip J. Lowe, Anne Kümmel, Christina Vasalou, Soichiro Matsushima and Andrej Skerjanec13.1 Introduction 17513.2 Methods 17613.2.1 Omalizumab, IgE, Itch, and Hives 17613.2.2 QGE031 and Omalizumab, IgE, Basophil FcεR1 and Surface IgE, and Allergen Skin Prick Test Response 17813.2.3 Common Components 180            13.3 Results and Discussion 18113.3.1 Omalizumab Capture of IgE Reducing Itch and Hives 18113.3.2 QGE031 and Omalizumab Capture of IgE, Reducing Basophil FcεR1, Surface IgE, and Allergen Skin Reactivity 18513.4 Conclusions 191Acknowledgments 193References 19314 Target‐Driven Pharmacokinetics of Biotherapeutics 197Wilhelm Huisinga, Saskia Fuhrmann, Ludivine Fronton and Ben‐Fillippo Krippendorff14.1 Introduction 19714.2 Soluble and Membrane‐Bound Targets 19714.3 Whole‐Body Target‐Mediated Drug Disposition Models and Their Approximations 19814.3.1 Generic Whole‐Body TMDD Model 19814.3.2 Characteristics of Target‐Driven PK Profiles 19914.3.3 Location of the Target: Central versus Peripheral Compartment 20014.3.4 Parameter Identifiability and Model Reduction 20014.3.5 Extended Michaelis–Menten Approximation with Target Turnover 20114.3.6 Michaelis–Menten Approximation with Target Turnover 20214.3.7 Extended Michaelis–Menten Approximation 20214.3.8 Michaelis–Menten Approximation 20314.3.9 Model Selection 20314.4 Cell‐Level Target‐Mediated Drug Disposition Models 20314.4.1 Cell‐Level TMDD Model with a Single‐Cell Type 20414.4.2 Cell‐Level TMDD Model with Normal and Tumor Cells 20414.5 Simplified Physiologically Based Pharmacokinetic Model for mAbs 20614.5.1 Target‐Independent Pharmacokinetics 20614.5.2 Drug–Target Interaction 20814.6 Conclusion: Looking at Data Through Models 209Acknowledgment 209References 20915 Target‐Driven Pharmacokinetics of Biotherapeutics 213Guy M.L. Meno‐Tetang15.1 Introduction 21315.2 Peptide–FC Fusion Proteins 21415.3 Monoclonal Antibodies (mAbs) 21515.3.1 Antibodies Absorption 21515.3.2 Antibodies Distribution 21515.3.3 Mechanism of mAb Elimination 21615.3.4 Antibody–Drug Conjugates 21715.3.5 Recombinant Proteins 21815.4 Parameters Controlling Target‐Driven Nonlinear Pharmacokinetics of Biotherapeutics 21815.4.1 Target Localization 21815.4.2 Target Affinity 21915.4.3 Target Turnover 21915.4.4 Target Baseline and Disease Progression 21915.4.5 Off‐Target Binding 22015.5 Impact of Target‐Driven Nonlinear Pharmacokinetics of Biotherapeutics on Halometric Scaling 22015.5.1 Ethnic Differences 22015.6 Conclusions and Perspectives 220References 22116 Tumor Effect‐Site Pharmacokinetics: Mechanisms and Impact on Efficacy 225Greg M. Thurber16.1 Introduction 22516.2 Tumor Pharmacokinetics 22516.2.1 Tissue Physiology, Fluid Balance, and Macromolecular Transport 22516.2.2 Tumor Transport—An Overview 22616.2.3 Mechanisms of Tumor Transport 22716.2.4 Revisiting Tumor Transport Theory 22916.2.5 Impact of Drug Targeting Parameters on Distribution 23116.2.6 Experimental Validation and Comparison with Small Molecules 23216.3 Impact of Tumor Pharmacokinetics on Efficacy 23216.3.1 Overview of Cell‐Killing Mechanisms 23216.3.2 Pharmacokinetic Impact on Efficacy 23316.4 Conclusions 235References 23617 Brain Effect Site Pharmacokinetics: Delivery of Biologics Across the Blood–Brain Barrier 241Gert Fricker and Anne Mahringer17.1 Cytotic Processes at the BBB 24317.2 Receptors at the BBB as Targets for Biologics 24317.2.1 Transferrin Receptor 24317.2.2 Insulin Receptor 24417.2.3 Insulin‐Like Growth Factor Receptor 24417.2.4 LDL Receptor 24417.2.5 Low Density Lipoprotein Receptor‐Related Protein 1 24517.2.6 Low Density Lipoprotein Receptor‐Related Protein 2 24517.2.7 Leptin Receptor (OBR) 24517.2.8 Receptor of Advanced Glycation Endproducts 24517.2.9 Scavenger Receptor(SR) 24617.3 “Trojan Horse” Approaches to Target BBB Receptors 24617.4 Colloidal Carriers for Drug Delivery 24817.5 Other Brain‐Directed Carriers 24917.6 Stem Cell‐Mediated Drug Delivery 25017.7 Focused Ultrasound and Microbubbles 25117.8 Conclusions and Perspectives 251References 25118 Molecular Pathology Techniques in the Preclinical Development of Therapeutic Biologics 257Thierry Flandre, Sarah Taplin, Stewart Jones and Peter Lloyd18.1 Introduction 25718.2 Target Expression Profiling 25918.2.1 Detection of DNA/RNA‐Based Target Expression Using Whole Tissue Extracts 25918.2.2 Detection of Protein‐Based Target Expression Using Whole Tissue Extracts 26018.2.3 Localization of DNA/RNA and Protein‐Based Target Expression at the Cellular Level Using Tissue Sections 26218.3 Off‐Target Binding of the Therapeutic Biologic Reagent 26318.3.1 Tissue Cross‐Reactivity Study 26318.3.2 Protein Microarray 26418.3.3 Cell Microarray Technology (Retrogenix) 26418.3.4 Protein Pull‐Down Assays 26418.4 Biodistribution of Therapeutic Biologic Reagent 26418.4.1 Whole‐Body Autoradiography 26418.4.2 Biodistribution: Immunohistochemistry Methods for Protein‐Based Therapeutic Products 26518.4.3 Biodistribution: Quantitative PCR Methods DNA/RNA‐Based Therapeutic Products 26518.5 Discussion 26518.5.1 Considerations in the Interpretation of Molecular Pathology‐Based Data 26518.5.2 Examples of Molecular Pathology Methods Used in Preclinical Development 26618.6 Conclusion 267References 26719 Labeling and Imaging Techniques for Quantification of Therapeutic Biologics 271Julie K. Jang, David Canter, Peisheng Hu, Alan L. Epstein and Leslie A. Khawli19.1 Introduction 27119.2 New and Conventional Methods for Labeling of Biologics 27219.2.1 Choice of Labels 27219.2.2 Labeling Strategies of Biologics 27719.3 Molecular Imaging for the Study of PK and Biodistribution of Biologics 28519.3.1 SPECT Imaging 28619.3.2 PET Imaging 28619.3.3 Optical Imaging 28819.4 Conclusions and Perspectives 288References 28920 Knowledge of ADME of Therapeutic Proteins in Adults Facilitates Pediatric Development 295Omoniyi J Adedokun and Zhenhua Xu20.1 Introduction 29520.2 Comparative Evaluation of ADME of Therapeutic Proteins between Adults and Children 29620.2.1 Absorption 29620.2.2 Distribution 29720.2.3 Metabolism and Elimination 29720.3 Extrapolation of Efficacy from Adults to Pediatric Patients 29820.3.1 No Extrapolation Approach 29820.3.2 Partial Extrapolation Approach 29820.3.3 Full Extrapolation Approach 29920.4 Pediatric Dose Strategies 30020.4.1 Body Weight‐Based (Linear) Dose‐Adjustment Approach 30020.4.2 BSA‐Based (Linear) Dose‐Adjustment Approach 30420.4.3 Tiered‐Fixed Dose‐Adjustment Approach 30420.4.4 Hybrid Dose‐Adjustment Approach 30420.4.5 Other Dose‐Adjustment Approaches 30420.5 Sample‐Size Determination for Pediatric Studies 30420.6 Modeling and Simulation in Pediatric Drug Development Facilitated by Existing Adult Models 30520.6.1 Modeling and Simulation Framework for Therapeutic Proteins in Pediatric Drug Development 30520.6.2 Examples of the Application of Modeling and Simulation in the Development of Therapeutic Proteins in Pediatric Patients 30720.7 Future Directions 309References 30921 LC/MS versus Immune‐Based Bioanalytical Methods in Quantitation of Therapeutic Biologics in Biological Matrices 313Bo An, Ming Zhang and Jun Qu21.1 Introduction 31321.2 Comparison of the Characteristics in Method Development 31421.2.1 Method Development Time 31421.2.2 Specificity 31421.2.3 Characteristics of Method Development 31421.3 Comparison of Assay Performance 31621.3.1 Sample Preparation 31621.3.2 Calibration Curve and Linearity Range 31821.3.3 Applicability 31821.3.4 Accuracy 31921.3.5 Sensitivity 31921.3.6 Reproducibility 32121.4 Application of LBA and LC/MS in the Analysis of Therapeutic Proteins 32321.4.1 Quantification of mAb in Plasma and Tissues 32321.4.2 Application in Multiplexed Analysis 32321.4.3 Characterization of Antibody–Drug Conjugates (ADC) 32421.5 Summary and Future Perspective 324References 32422 Biosimilar Development: Nonclinical and Clinical Strategies and Challenges with a Focus on the Role of PK/PD Assessments 331Susan Hurst and Donghua Yin22.1 Introduction 33122.2 Aspects of Biosimilarity 33222.3 Biosimilars’ Regulatory/Historical Perspective 33322.3.1 European Union 33322.3.2 EMA Nonclinical In Vivo Considerations 33322.3.3 EMA Clinical Considerations (Related to PK/PD) 33422.3.4 United States 33422.3.5 FDA Nonclinical In Vivo Considerations 33522.3.6 FDA Clinical Considerations (Related to PK/PD) 33522.3.7 The WHO and Other Global Markets 33622.4 Nonclinical Assessments in the Development of Biosimilars 33622.4.1 Biosimilars Nonclinical Development 33622.4.2 Designing the Nonclinical In Vivo Study 33622.4.3 Designing the Nonclinical Study: Immunogenicity/Bioanalytical 33722.4.4 Designing the Nonclinical In Vivo Study—PK and PD Focus 33722.4.5 Designing the Nonclinical In Vivo Study—No Relevant Nonclinical Species 33822.5 Clinical PK and PD Assessments in the Development of Biosimilars 34022.5.1 Biosimilars Clinical Development 34022.5.2 Bioanalytical Assays for Biosimilars PK and PD Investigations 34122.5.3 Design Considerations for Phase I PK and PD Similarity Studies 34122.5.4 PK Similarity Study of PF‐05280014, a Proposed Biosimilar to Trastuzumab: An Example 34222.5.5 Extrapolation of Clinical Data 34222.6 Concluding Remarks 344Acknowledgments 344References 34423 ADME Processes in Vaccines and PK/PD Approaches for Vaccination Optimization 347José David Gómez‐Mantilla, Iñaki F. Trocóniz and María J. Garrido23.1 Introduction 34723.1.1 Vaccine Development 34723.1.2 Types of Vaccines 34823.1.3 Basic Immunological Mechanism of Vaccine Development 34823.2 Biopharmaceutic Considerations on Vaccine ADME Processes 35023.3 Vaccines and ADME Processes 35023.3.1 Effect of Vaccine Formulation on ADME 35123.3.2 Effect of Route of Administration 35323.3.3 Metabolism and Excretion 35723.3.4 PK Considerations 35723.4 Mathematical Modeling for Vaccine Optimization in Cancer Treatment 36023.5 Systems Vaccinology: Application of Systems Biology in Personalized Vaccination 36223.6 Concluding Remarks 363References 36324 Drug Development Strategies for Therapeutic Biologics: Industry Perspectives 369Theresa Yuraszeck and Megan Gibbs24.1 Introduction 36924.1.1 Biologics Properties and Classification 37024.1.2 Assay Development and Validation 37224.2 Preclinical Development 37224.2.1 FIH Starting Dose 37424.3 Clinical Development 37524.3.1 Intrinsic and Extrinsic Factors 37524.3.2 Special Populations: Renal and Hepatic Impairment 37624.3.3 Special Populations: Pediatrics 37624.4 Biosimilars 37724.5 Emerging Markets 37724.6 Conclusions 378References 37925 Review: The Critical Role of Clinical Pharmacology in the Development of Biologics 385Liang Zhao, Diane Wang, Ping Zhao, Elizabeth Y. Shang, Yaning Wang and Vikram Sinha25.1 Introduction 38525.2 PK and PD of Biologics 38525.2.1 Structural Difference between SMDs and Biological Products 38525.2.2 Route of Administration and Absorption 38625.2.3 Distribution 38625.2.4 Metabolism and Elimination 38625.2.5 mAb Distribution 38625.2.6 Catabolism and Elimination 38725.2.7 Other Biologics 38725.3 Critical Role of Clinical Pharmacology and Related Regulatory Guidance for Biologics Development 38725.3.1 First‐in‐Human (FIH) Dose Determination and Study Design 38725.3.2 Critical Considerations from a Standpoint of Clinical Pharmacology in Biologics Development 38825.4 Model‐Based Drug Development for Biologics 39325.4.1 Fixed Dosing versus Body Size‐Adjusted Dosing 39425.4.2 Mechanism‐ and Physiologically Based Models for mAbs 39425.4.3 Utility of Meta‐Analysis 39525.4.4 Utility of Case–Control Analysis in Biologics Development 39625.5 Conclusions 39725.6 Disclaimer 397References 39726 Investigating the Nonclinical ADME and PK/PD of an Antibody–Drug Conjugate: A Case Study of ADO‐Trastuzumab Emtansine (T‐DM1) 401Jay Tibbitts26.1 Introduction 40126.2 Importance of ADME for ADCs 40226.3 T‐DM1 Bioanalytical Strategy and Methods 40326.4 Ex Vivo Linker Stability 40426.5 Plasma PK 40426.6 Distribution of T‐DM1 40626.7 T‐DM1 Catabolism and Elimination 40626.8 T‐DM1 Nonclinical PK/PD 40826.9 Conclusions 409References 40927 Use of PK/PD Knowledge in Guiding Bispecific Biologics Research and Development 413Andreas Baumann, Saileta Prabhu and Jitendra Kanodia27.1 Introduction 41327.2 Structural Formats and Generation of Bispecific Biologics 41527.3 Biochemistry and Pharmacology of Bispecifics 41627.3.1 Affinity 41627.3.2 Avidity 41627.4 Pharmacokinetics 41627.4.1 PK Assay Strategies Employed for the Development of bsAbs 41727.4.2 Immunogenicity Strategies Employed for the Development of bsAbs 41827.5 Pharmacokinetic–Pharmacodynamic Model‐Informed Design of bsAbs 41827.6 Application of PK/PD in the Research and Development of Bispecific Biologics: Case Examples 41927.6.1 Anti‐TfR/BACE1 to Improve Therapeutic Antibody Transport across the Blood–Brain Barrier 41927.6.2 PK Characterization to Optimize bsAb Molecule Design and Selection for Ophthalmology 42027.6.3 Pharmacokinetic Studies during Development of a Bispecific T‐Cell Engager 42127.7 Outlook 421References 422Index 427

"At the outset, one�s impressed with the scope of the book; it provides an outline of very diverse topics starting with the basics of protein engineering and how these are used to design and manipulate the ADME properties of recombinant and synthetic proteins...The authors have to be congratulated on their endeavor to stitch these topics together in a single book...With such a wide range of topics, even an experienced scientific practitioner in this area is likely to find something new to engage them and expand their knowledge...In summary, an excellent and comprehensive book for beginners to the CP/PK area to acquaint themselves with the area of biologics (specifically mAb) CP/PKPD principles and for experienced CP/PK scientists for reference." (CPT: Pharmacometrics & Systems Pharmacology, March 2017)