دانلود کتاب Introduction to Antibody Engineering

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Preface Contents 1: Introduction by the Editors 2: Antibodies: A History of Their Discovery and Properties What You Will Learn in This Chapter 2.1 Introduction 2.2 Early Beginnings 2.3 Serum as the Protection Matrix 2.4 Specificity and the Nature of Proteins 2.5 Theories of Protein Structure 2.6 Antibody Sequences: Homogeneous or Heterogeneous? 2.7 γ-Globulin: Isotypes and Allotypes 2.8 The Structural Basis of Antibody Recognition Revealed 2.9 The Origins of Antibody Diversity 2.10 The Fc Region and Effector Functions 2.11 The Modern Era 2.12 The Antibody Engineering Revolution References 3: Monoclonal AntibodiesMonoclonal antibodies (mAbs) and HybridomasHybridomas What You Will Learn in This Chapter 3.1 The First Monoclonal Antibodies 3.2 Sequence, Structure and Function of Antibodies 3.2.1 Overall Structure 3.2.2 Variable Domains 3.2.3 Constant Domains 3.3 The Hybridoma Method 3.3.1 The Starting Point: Antibody-Producing B-Cells 3.3.2 ImmunizationImmunizations 3.3.3 Myeloma Cell Lines Suitable for Fusion 3.3.4 Cell FusionCell fusion 3.3.5 Identification of Individual Hybridoma Clones 3.3.6 Monoclonality 3.4 From Mouse to Human Monoclonal Antibodies 3.4.1 Chimeric Antibodies 3.4.2 Nomenclature of Monoclonal Antibodies 3.4.3 Humanized Antibodies 3.4.4 Fully Human Monoclonal Antibodies 3.5 Antibody Fragments Questions Take Home Message References 4: Antibody Display Systems What You Will Learn in This Chapter 4.1 Introduction 4.2 Phage DisplayPhage display 4.3 YeastYeast Surface Display 4.4 Mammalian DisplayMammalian display 4.5 E. coli DisplayE. coli display 4.6 Ribosome Display 4.7 cDNA DisplaycDNA display 4.8 B-Cell Cloning Take Home Message References 5: Transgenic AnimalsTransgenic animals for the Generation of Human Antibodies What You Will Learn in This Chapter 5.1 The Concept of Using Transgenic Animals to Generate Human Therapeutic Antibodies 5.2 Strategies in Developing Transgenic Platforms for Human Antibody Discovery 5.2.1 Transgenic Strategies 5.2.2 Animals with Knockout of Endogenous Ig Production 5.2.3 Human IgH Gene Loci in Transgenic Constructs 5.2.4 Human Igĸ and Igλ Gene Loci in Transgenic Constructs 5.3 Examples of Currently Available Transgenic Platforms for Human Antibody Discovery 5.3.1 HuMAb-MouseHuMab-Mouse and XenoMouse 5.3.2 Tc Mouse, Tc Bovine and Tc Goat (Caprine) 5.3.3 OmniRat, OmniMouseOmniMouse and OmniChicken 5.3.4 VelociMouseVelociMouse, Kymouse and Trianni Mouse 5.3.5 Transgenic Platforms Expressing Different Formats of Antibodies 5.3.5.1 OmniFlicOmniFlicand OmniClicOmniClic 5.3.5.2 HCAb Transgenic Mice (Harbour Biomed), Humabody VH Platform and UniRat 5.4 Strategies in Antibody Discovery from Transgenic Platforms Take Home Messages Further Reading References 6: Applications of Antibodies in Therapy, Diagnosis, and Science What You Will Learn in This Chapter 6.1 Application of Antibodies in Therapy 6.1.1 Cetuximab 6.1.2 Trastuzumab 6.1.3 Rituximab 6.1.4 Ipilimumab 6.1.5 Nivolumab 6.1.6 PembrolizumabPembrolizumab (Keytruda) 6.1.7 Avelumab 6.1.8 Adalimumab 6.1.9 BlinatumomabBlinatumomab (Blincyto) 6.1.10 Emicizumab 6.2 Applications of Antibodies in Diagnosis 6.3 Application of Antibodies in Science 6.3.1 Immunoprecipitation 6.3.2 Chromatin ImmunoprecipitationChromatin immunoprecipitation (ChIP) 6.3.3 Western Blotting 6.3.4 Enzyme-Linked Immunosorbent Assay (ELISAEnzyme-linked immunosorbent assay (ELISA)) 6.3.5 ImmunohistochemistryImmunohistochemistry (IHC)/ImmunocytochemistryImmunocytochemistry (ICC) 6.3.6 Immuno-PCR and Proximity Ligation Assay 6.3.7 Flow CytometryFlow cytometry 6.3.8 Mass SpectrometryMass spectrometry (MS) Take Home Message References Further Reading 7: Bispecific Antibodies What You Will Learn in This Chapter 7.1 Introduction Questions 7.2 History of Bispecific Antibodies Questions 7.3 Mode of Action of Bispecific Antibodies Today 7.3.1 BsAbs for Bridging Different Cell Types 7.3.2 Signaling Inhibition by Bridging Receptor Molecules 7.3.3 Overcoming Ligand Redundancy 7.3.4 Targeting Two Epitopes of the Same Antigen: Biparatopic bsAbs 7.3.5 Enzyme Mimetics 7.3.6 BsAbs Enabling Transport: Piggyback Molecules Questions 7.4 Formats of Bispecific Antibodies 7.4.1 Fragment-Based Bispecific Antibodies 7.4.2 Symmetric Ab Formats 7.4.3 Asymmetric bsAb Formats Questions 7.5 Outlook for Bispecific Antibodies 7.6 Conclusion Take Home Messages References 8: Antibody-Drug Conjugates What You Will Learn in This Chapter 8.1 Introduction to ADCs 8.2 Milestones of ADC Development 8.3 Targets and Antibodies Utilized for ADCsAntibody-drug conjugates (ADCs) 8.4 Cytotoxic ADC Payloads 8.5 ADC Linkers 8.6 Conjugation Technologies for ADC Generation Take Home Messages References 9: Alternative Binding Scaffolds: Multipurpose Binders for Applications in Basic Research and Therapy What You Will Learn in This Chapter 9.1 What Are Alternative Binding Scaffolds, What Are Their Features, and What Is Their Potential? 9.2 Details on the Most Advanced Alternative Binding Scaffolds 9.2.1 Tenth Type III Domain of Fibronectin (Monobodies, Adnectins) 9.2.2 Affibodies 9.2.3 Affitins/Nanofitins 9.2.4 Avimers 9.2.5 Cysteine-Knot Miniproteins (Knottins) 9.2.6 Designed Ankyrin Repeat Proteins 9.2.7 Fynomers 9.2.8 Kunitz Domain Inhibitors 9.2.9 Lipocalins (Anticalins) 9.3 Alternative Binding Scaffolds in the Clinic 9.4 Alternative Binding Scaffolds as Tools in Basic Research and Beyond 9.5 Future Directions Take Home Messages References 10: Chimeric Antigen Receptor (CAR) Redirected T Cells What You Will Learn in This Chapter 10.1 The Prototype Chimeric Antigen Receptor (CAR, T-Body, Immunoreceptor) 10.2 Modular Composition of a CAR: The Extracellular CAR Domains 10.2.1 The Binding Domain 10.2.2 The Spacer Domain 10.2.3 The Transmembrane Region 10.2.4 Intracellular Signaling Domains 10.3 TRUCK: The ``Fourth Generation´´ CAR T Cell 10.4 CAR T Cells with Dual Specificities, Combinatorial Antigen Recognition, and Conditional CARs 10.5 Universal CARs with Engrafted Multiple Antigen Specificities 10.6 Switch CARs Convert a Suppressor into an Activation Signal 10.7 Inhibitory CARs: iCARs 10.8 Allogeneic CAR T Cells and CAR NK Cells 10.9 Manufacturing CAR T Cells for Clinical Applications 10.10 Adoptive Therapy with CAR T Cells Induces Lasting Remissions in Hematologic Malignancies 10.11 The Challenges of CAR T Cells in Treating Solid Cancer 10.12 CAR T Cell Therapy Is Associated with Toxicities 10.12.1 Systemic Toxicities 10.12.2 ``On-Target Off-Tumor´´ Toxicities 10.12.3 ``Off-target Off-tumor´´ Toxicities 10.12.4 Strategies to Ameliorate CRS 10.13 Challenges in CAR T Cell Therapy 10.13.1 Which Is the Best Tumor-Selective Antigen Suitable for Targeting? 10.13.2 How to Optimize the CAR Architecture? 10.13.3 How to Establish Long-Term Cancer Control After CAR T Cell Therapy? 10.13.4 Which T Cell Subset Provides Long-Term Tumor Control? 10.13.5 How Can CAR T Cell Manufacturing Be Adapted to an Increasing Number of Patients? 10.13.6 How to Balance CAR T Cell Efficacy and Side Effects? 10.13.7 Do We Need Specific Pre-conditioning for Each Cancer Type? 10.13.8 How to Activate the Immune Network to Induce a Broad Inflammatory Antitumor Response? 10.14 CAR T Cells for the Treatment of Other Diseases Take Home Messages References 11: Improvement of Key Characteristics of Antibodies What You Will Learn in This Chapter 11.1 Improving the Natural Functions of Antibodies to Create Therapeutics 11.2 Antigen Binding 11.2.1 Binding Epitope and Affinity 11.2.2 Creating a Therapeutic Antibody with pH Sensitivity or `pH Switch´ 11.3 Improving and Optimising the Interactions with Fc Receptors 11.4 Complement Activation and Inactivation 11.5 Improving Serum Half-Life to Decrease Dosing Frequency 11.6 Immunogenicity of Therapeutic Antibodies 11.7 Antibody Fragments 11.8 Improving Biophysical Properties of Therapeutic Antibodies 11.8.1 Aggregation 11.8.2 Thermal Denaturation 11.8.3 Fragmentation, Deamidation and Oxidation 11.8.4 Computational Design Tools Take Home Messages References 12: Engineering Therapeutic Antibodies for Development What You Will Learn from This Chapter 12.1 Introduction 12.2 Safety Considerations 12.3 Examples of Target-Dependent Side Effects of mAbs 12.4 Immunogenicity of Biotherapeutics 12.5 What Causes Immunogenicity? 12.6 Mechanisms Leading to an ADA Response 12.6.1 T Cell-Dependent Immune Response 12.7 T Cell-Independent Immune Response 12.8 Clinical Consequences of Immunogenicity 12.9 Engineering mAbs for Safety and Minimal Immunogenicity 12.10 Humanization 12.11 Selection of Isotypes 12.12 Heterogeneity of Therapeutic mAbs 12.13 Quality Attributes of mAbs Can Impact Safety and Efficacy 12.14 Protein Engineering to Control mAb Variants 12.15 Improved Manufacturability to Control mAb Variants 12.16 mAb Industrial Manufacturing 12.17 Considerations for Intended Use and mAb Formulation into Drug Product 12.18 Formulation Development 12.19 Closing Remarks Take Home Messages References 13: Eukaryotic Expression Systems for Upstream Processing of Monoclonal Antibodies What You Will Learn in This Chapter 13.1 Introduction 13.1.1 Antibodies and Different Antibody Formats 13.1.2 Product Quality Attributes 13.1.2.1 Glycosylation 13.1.2.2 Charge Distribution 13.1.2.3 Molecular Size 13.1.2.4 Oxidation 13.1.2.5 Structure 13.2 Antibody Production in Mammalian Cells 13.2.1 Host Cell Lines 13.2.2 Cell Culture Medium 13.2.3 Environmental Cultivation Parameters 13.2.4 Mode of Bioreactor Operation 13.3 Antibody Production in Yeast and Filamentous Fungi 13.3.1 General Characteristics of the Expression Systems 13.3.2 Glycosylation and Glycoengineered Production Strains 13.3.3 Antibody Production in Yeast 13.3.4 Antibody Production in Filamentous Fungi 13.4 Conclusion Take Home Messages References 14: Antibody Validation What You Will Learn in This Chapter 14.1 Introduction 14.1.1 State of the Art and Problem Setting Questions 14.1.2 Advantages of Polyclonal Antibodies Questions 14.2 Cornerstones for Antibody Validation for Different Scientific Applications 14.2.1 Standards for Reporting the Use of Antibodies in Scientific Publications Questions 14.2.2 Publicly Available Antibody Databases Questions 14.2.3 Minimum Information About a Protein Affinity Reagent Proposal Questions 14.3 Scientific Incentives for Antibody Validation Questions 14.4 The Human Protein Atlas 14.4.1 Introduction to the Human Protein Atlas 14.4.2 History of Human Protein Atlas 14.4.3 Standard Antibody Validation 14.4.4 Enhanced Antibody Validation Questions 14.5 Start-off Simple: 10 Validation Rules for Diagnostic and Analytical Antibodies Questions 14.6 Conclusion Take Home Messages References Index