Antibodies for Treating. Cancer Basics, Development, and Applications

Description

Preface Contents About the Author 1: Life-Saving Antibodies: History of Immunization 1.1 Introduction 1.2 Variolation Introduction of Variolation to England and Europe Introduction of Variolation to North America Variolation of the Continental Army 1.3 Vaccination Against Smallpox Eradication of Smallpox 1.4 Vaccinations Against Other Infectious Diseases The Tuberculin Scandal 1.5 Healing Diphtheria with Horse Serum 1.6 Antigen (Antibody-Generating Substance) 1.7 Antibodies Are Produced in B Lymphocytes (B Cells) 1.8 Current Vaccines COVID-19 Vaccine Ebola Vaccine Passive Immunization Selected Literature 2: Antibodies and the Immune System 2.1 Introduction 2.2 The Immune Response 2.3 Cellular Components of the Immune System 2.4 Innate Immune System Pattern Recognition by the Innate System The Complement Cascade Natural Killer Cells Recognition of Self and Nonself 2.5 Adaptive Immune System MHC Complex (Major Histocompatibility Complex) Lymphocytes B Lymphocytes (B Cells) Activation of Mature B Cells T Lymphocytes T-Cell Receptor (TCR) Unconventional T Cells Helper T Cells Cytotoxic T Cells Costimulatory Molecules 2.6 Cytokine Signaling 2.7 Immunoregulation SOCS (Suppressor of Cytokine Signaling) Proteins Selected Literature 3: Current Approaches for Immunizing Against Cancer 3.1 Introduction 3.2 Inoculation with Immunostimulants 3.3 Viruses and Cancer Vaccine Against the Papillomavirus Vaccination Against Hepatitis B Cell Vaccine Against a Tumor-Associated Antigen 3.4 Nucleic Acid-Based Vaccines Delivery of mRNA Mutanome Engineered RNA Immunotherapy (MERIT): Personalized Therapy 3.5 Vaccination with a Ubiquitous Tumor Marker? Selected Literature 4: Generation, Structure, and Function of Antibodies 4.1 Introduction 4.2 Elucidation of the Antibody Structure 4.3 Antibody Diversity 4.4 Antibody Gene Rearrangement 4.5 Somatic Hypermutation (SHM) 4.6 Class Switch Recombination (CSR) 4.7 Role of Antibodies 4.8 Binding Sites for Antibody Fc Domains 4.9 IgG Fc Receptors (FcγR) 4.10 Classes of Immunoglobulins 4.11 Long Half-Life of IgG Antibodies 4.12 Antibody Glycosylation 4.13 Chain Folding of an Antibody 4.14 Antibody Terminology Selected Literature 5: Of Mice and Men: Production of Therapeutic Antibodies 5.1 Introduction 5.2 Myeloma Cell Cultures 5.3 Fused Myeloma Cell Lines 5.4 First Hybridoma 5.5 Cloned B Lymphocytes 5.6 Hybridoma Technology: Monoclonal Antibodies of Known Specificity 5.7 Hybridoma Selection 5.8 First Approved Therapeutic Antibody 5.9 Humanization of Monoclonal Antibodies 5.10 Human Antibodies from Transgenic Animals 5.11 Human Antibody Libraries 5.12 Selection of a Specific Antibody Using Phage Display 5.13 Production of Therapeutic Antibodies 5.14 GMP Conditions (Good Manufacturing Practice) Selected Literature 6: Mediation of Tumor Cell Death by Naked Antibodies 6.1 Introduction 6.2 Antibodies Targeting Antigens on Tumor Cells Death Signals: Apoptosis Fc-Mediated Effector Functions 6.3 Activating Fcγ Receptors Enhancement of Fc Effector Functions Rituxan/MabThera for Treating Non-Hodgkin’s Lymphoma (NHL) 6.4 Growth Inhibition of Tumor Cells Herceptin for Treating Breast Cancer Erbitux for Treating Colorectal Cancer 6.5 Antibodies Targeting Angiogenesis (Blood Vessel Formation) Avastin for Treating Solid Tumors Cyramza for Treating Colorectal Cancer 6.6 Activation of Immune Cells by Monoclonal Antibodies Tumor-Infiltrating Lymphocytes Antibodies for Activating Costimulatory Receptors on T Cells The TeGenero Bombshell 6.7 Antibodies Targeting Immune Checkpoints (ICs) on T Cells Successful Combination Therapy of Opdivo and Yervoy 6.8 Mechanisms of Resistance Immunoediting Epithelial-Mesenchymal Transition (EMT) Transforming Growth Factor-ß (TGF-ß) Tumor Microenvironment Indoleamine 2,3-Dioxygenase (IDO) “Don’t Eat Me” Signaling by CD47 6.9 Hot and Cold Tumors Selected Literature 7: Antibodies as Magic Bullets 7.1 Introduction 7.2 Toxins: “Shaken, Not Stirred” 7.3 Immunotoxins Uptake of Toxins in Cancer Cells Treatment of Glioblastoma with a Transferrin Immunotoxin Lumoxiti for Treating Hairy Cell Leukemia Single-Arm Open-Label Pivotal Phase III Clinical Trial Treatment of Solid Tumors with Immunotoxins Shedding of Tumor Markers 7.4 Antibody-Drug Conjugates (ADCs) ADC Conjugation ADC Linker Examples of ADC Linker Cleavage Sites Hydrazone Linker Cathepsin B Linker Disulfide Linker Drug Payloads 7.5 DNA-Damaging ADCs Mylotarg for Treating Acute Myeloid Lymphoma (AML) Besponsa for Treating Relapsed Acute Lymphoblastic Leukemia (B-ALL) 7.6 Microtubule Destabilizing ADCs Adcetris for Treating Hodgkin’s Lymphoma Polivy for Treating Diffuse Large B-Cell Lymphoma (DLBCL) Kadcyla for Treating Metastatic Breast Cancer Enhertu for Treating Metastatic Breast Cancer Trodelvy for Treating Triple-Negative Breast Cancer Padcev for Treating Bladder Cancer 7.7 Antibody-Directed Enzyme Prodrug Therapy (ADEPT) 7.8 Cytokine Payloads 7.9 Antibodies with Radioactive Payloads Pre-targeting Tumor Cells for Radiotherapy 7.10 Radiolabeled Antibodies for Treating Follicular Lymphomas (FL) Treatment of Solid Tumors with Radioactively Labeled Antibodies Selected Literature 8: Novel Modular Antibodies 8.1 Introduction 8.2 Single-Chain Fv Antibodies (scFv) 8.3 Modular Multivalent Antibodies 8.4 The Diabody Structure 8.5 Single-Domain Antibodies (sdAb) from Sharks, Camels, and Humans 8.6 Binding Modules Comprising Non-Ig Protein Scaffolds: Antibody Mimetics 8.7 Size Matters Selected Literature 9: Recruiting Killer Cells for Cancer Therapy 9.1 Introduction 9.2 Recruitment of Killer Cells with Bispecific Antibodies Quadromas Removab (Catumaxomab) 9.3 Methods to Facilitate Desired Chain Pairing 9.4 Addition of Binding Domains to Heavy and Light Chains 9.5 Two-in-One Antibodies 9.6 Peptide-Fused Antibodies 9.7 Bispecific Antibodies Comprising Chains of Antibody Variable Domains Blincyto (Blinatumomab) for Treating Acute Lymphoblastic Leukemia (ALL) Recruitment of NK Cells 9.8 Risks of Bispecific Antibodies 9.9 Targeting Cancers with Chimeric Antigen Receptor (CAR)-T Cells 9.10 Construction of CARs 9.11 Kymriah for Treating B-ALL: The First Gene Therapy to Be Approved by the FDA 9.12 Yescarta for Treating Diffuse Large B-Cell Lymphoma (DLBCL) 9.13 Novel Approaches to Optimize CAR-T Therapy Dual Chain CAR (dcCAR) and Antibody Mimetics T-Cell Receptor Fusion Constructs (TRuCs) Universal Immune Receptors (UIRs) Prevention of T-Cell Exhaustion and Immunosuppression Synthesis of Orthogonal Cytokines and Receptors Deletion of Regnase-1 Priming CAR-T Cells by Antigen-Presenting Cells (APCs) 9.14 Allogenic CARs 9.15 NK CARs and Macrophage CARs 9.16 T Cells Transduced with a Cancer-Specific TCR 9.17 Safety Switches Selected Literature 10: Cancer Incidence: Market for Therapeutic Antibodies 10.1 Introduction 10.2 Market for Treating Cancer with Antibodies 10.3 Cancer Mortality in United States 10.4 Comparison of Mortality Rates Between China and the United States/United Kingdom 10.5 Risk of Developing Cancer 10.6 Cancer Therapies 10.7 Acquisition of Genentech by Roche 10.8 Acquisition of Antibody Technologies 10.9 From Antibody Technology Platforms to Product Candidates 10.10 From Product Candidates to Therapeutics Clinical Trial Approval 10.11 Help from MABEL to Calculate the Starting Dose 10.12 Cost Containment: NICE to Have? 10.13 QALY 10.14 Cost Reduction with Biosimilars Selected Literature 11: Outlook 11.1 Introduction 11.2 A New Generation of Antibodies for Cancer Therapy 11.3 Targets of mAbs in Late-Stage Clinical Development LAG-3 TIM-3 Claudin-18.2 Fibronectin Extra Domain B CEACAM5 Folate Receptor 1 4-1BB Tissue Factor 11.4 Trends in Molecular Formats of Approved and Late-Stage mAbs 11.5 Immune Checkpoint Inhibitors 11.6 CRISPR-Cas9 Gene Editing 11.7 CARs Versus Bispecific Antibodies 11.8 Inhibitors of Epigenetic Changes 11.9 Tumor Vaccines 11.10 Conclusion Selected Literature