Antibodies for Treating. Cancer Basics, Development, and Applications

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