Efnisyfirlit

• Contents
• Preface
• Abbreviations
• Contributors
• 1: Molecular Biotechnology: From DNA Sequence to Therapeutic Protein
• Introduction
• Pharmaceutical Biotechnology, Why This Book, Why This Chapter?
• Economics and Use
• From an In Silico DNA Sequence to a Therapeutic Protein
• ■ Selection of a Therapeutic Protein
• ■ DNA Sequence
• ■ Selection of Expression Host
• ■ CopyDNA
• Box 1.1 ■ The Central Dogma of Molecular Biology
• ■ Cloning PCR Products into an Expression Vector
• Box 1.2. ■ Plasmids .
• Box 1.3 ■ DNA Sequencing .
• ■ Transfection of Host Cells and Recombinant Protein Production
• ■ Cell Culture
• ■ Purification; Downstream Processing
• Monoclonal Antibodies
• Yields
• Conclusion
• Self-Assessment Questions
• Recommended Reading and References
• 2: Biophysical and Biochemical Analysis of Recombinant Proteins
• Introduction
• Protein Structure
• „ Primary Structure
• „ Secondary Structure
• α-Helix
• β-Sheet
• Loops and Turns
• „ Tertiary Structure
• „ Forces
• Hydrophobic Interactions
• Hydrogen Bonds
• Electrostatic Interactions
• Van der Waals Interactions
• „ Hydration
• Protein Folding
• „ Techniques Specifically Suitable for Characterizing Protein Folding
• Protein Stability
• Analytical Techniques
• „ Blotting Techniques
• Transfer of Proteins
• Detection Systems
• „ Immunoassays
• ELISA
• „ Electrophoresis
• Polyacrylamide Gel Electrophoresis
• Isoelectric Focusing (IEF)
• 2-Dimensional Gel Electrophoresis
• Detection of Proteins Within Polyacrylamide Gels
• Capillary Electrophoresis
• „ Chromatography
• Size-Exclusion Chromatography
• Reversed-Phase High-Performance Liquid Chromatography
• Hydrophobic Interaction Chromatography
• Ion-Exchange Chromatography
• Other Chromatographic Techniques
• „ Bioassays
• „ Mass Spectrometry
• Concluding Remarks
• Self-Assessment Questions
• Further Reading
• 3: Production and Purification of Recombinant Proteins
• Introduction
• Upstream Processing
• ■ Expression Systems
• General Considerations
• Transgenic Animals
• Plants
• ■ Cultivation Systems
• General
• Single-Use Systems
• Fermentation Protocols
• ■ Cultivation Medium
• Downstream Processing
• ■ Introduction
• ■ Filtration/Centrifugation
• Filtration
• Centrifugation
• ■ Precipitation
• ■ Chromatography
• Introduction
• Chromatographic Stationary Phases
• Adsorption Chromatography
• Ion-Exchange Chromatography
• (Immuno)Affinity Chromatography
• Affinity Chromatography
• Immunoaffinity Chromatography
• Hydrophobic Interaction Chromatography
• Gel-Permeation Chromatography
• Expanded Beds
• Contaminants
• ■ Viruses
• ■ Bacteria
• ■ Cellular DNA
• ■ Protein Contaminants and Product Variants
• N- and C-Terminal Heterogeneity
• Conformational Changes/Chemical Modifications
• Glycosylation
• Proteolytic Processing
• Bacteria: Protein Inclusion Body Formation
• Commercial-Scale Manufacturing and Innovation
• Self-Assessment Questions
• References
• 4: Formulation of Biotech Products, Including Biopharmaceutical Considerations
• Introduction
• Microbiological Considerations
• „ Sterility
• „ Viral Decontamination
• „ Pyrogen Removal
• Excipients Used in Parenteral Formulations of Biotech Products
• „ Solubility Enhancers
• „ Anti-adsorption and Anti-aggregation Agents
• „ Buffer Components
• „ Preservatives and Antioxidants
• „ Osmotic Agents
• Shelf Life of Protein-Based Pharmaceuticals
• „ Freeze-Drying of Proteins
• „ Freezing
• „ Primary Drying
• „ Secondary Drying
• „ Other Approaches to Stabilize Proteins
• Delivery of Proteins: Routes of Administration and Absorption Enhancement
• „ The Parenteral Route of Administration
• „ The Oral Route of Administration
• „ Alternative Routes of Administration
• „ Examples of Absorption-Enhancing Effects
• Delivery of Proteins: Approaches for Rate-Controlled and Target Site-Specific Delivery by the Parent
• Approaches for Rate-Controlled Delivery
• „ Open-Loop Systems: Mechanical Pumps
• „ Open-Loop Systems: Osmotically Driven Systems
• „ Open-Loop Systems: Biodegradable Microspheres
• „ Closed-Loop Systems: Biosensor-Pump Combinations
• „ Protein Delivery by Self-Regulating Systems
• „ Protein Delivery by Microencapsulated Secretory Cells
• Site-Specific Delivery (Targeting) of Protein Drugs
• „ Anatomical, Physiological, and Pathological Considerations Relevant for Protein Targeting
• „ Soluble Carrier Systems for Targeted Delivery of Proteins
• Monoclonal Antibodies (MAB) as Targeted Therapeutic Agents: Human and Humanized Antibodies (See Also
• Bispecific Antibodies (See Also Chap. 7)
• Immunoconjugates: Combinations Between an Antibody and an Active Compound
• „ Potential Pitfalls in Tumor Targeting
• „ Nanotechnology at Work: Nanoparticles for Targeted Delivery of Proteins
• „ Perspectives for Targeted Protein Delivery
• Self-Assessment Questions
• References
• 5: Pharmacokinetics and Pharmacodynamics of Peptide and Protein Therapeutics
• Introduction
• Pharmacokinetics of Protein Therapeutics
• ■ Absorption of Protein Therapeutics
• Enteral Administration
• Parenteral Administration
• ■ Distribution of Protein Therapeutics
• Distribution Mechanisms and Volumes
• Protein Binding of Protein Therapeutics
• Distribution via Receptor-Mediated Uptake
• ■ Elimination of Protein Therapeutics
• Proteolysis
• Gastrointestinal Protein Metabolism
• Renal Protein Metabolism
• Hepatic Protein Metabolism
• Target-Mediated Protein Metabolism
• Modulation of Protein Disposition by the FcRn Receptor
• ■ Immunogenicity and Protein Pharmacokinetics
• ■ Species Specificity and Allometric Scaling
• ■ Chemical Modifications for Optimizing the Pharmacokinetics of Protein Therapeutics
• Pharmacodynamics of Protein Therapeutics
• ■ Direct Link PK/PD Models
• ■ Indirect Link PK/PD Models
• ■ Indirect Response PK/PD Models
• ■ Cell Life Span Models
• ■ Complex Response Models
• Conclusion
• Self-Assessment Questions
• References
• Further Reading
• 6: Immunogenicity of Therapeutic Proteins
• Introduction
• The New Paradigm
• The Immunological Response
• Factors Influencing Antibody Formation to Therapeutic Proteins
• „ Structural Factors
• „ Impurities
• „ Formulation
• „ Route of Administration
• „ Dose
• „ Patient Features
• „ Assays for Antibodies
• Issues Specifically Related to Monoclonal Antibodies
• Clinical Effects of Induced Antibodies
• Predicting and Reducing Immunogenicity
• „ Reducing Immunogenicity
• Conclusions
• Self-Assessment Questions
• References
• Further Reading
• 7: Monoclonal Antibodies: From Structure to Therapeutic Application
• Introduction
• Antibody Structure and Classes
• ■ Murine, Chimeric, Humanized, and Fully Humanized MABs
• ■ Key Structural Components of MABs
• ■ Modifying Fc Structures
• ■ Antibody Derivatives (F(ab’)2, Fab, Antibody Drug Conjugates) and Fusion Proteins
• How Do Antibodies Function as Therapeutics?
• ■ Direct Modulation of Target Antigen
• ■ Complement-Dependent Cytotoxicity (CDC)
• ■ Antibody-Dependent Cellular Cytotoxicity (ADCC)
• ■ Apoptosis
• Translational Medicine/Development Process
• ■ Preclinical Safety Assessment of MABs
• ■ Pharmacokinetics
• Absorption
• Distribution
• Antibody Clearance
• Therapeutic MAB–Drug Interactions
• ■ Prediction of Human PK/PD Based on Preclinical Information
• ■ PK/PD in Clinical Development of Antibody Therapeutics
• Pre-phase I Studies
• Identification of MOA and PD Biomarkers
• Role of Surrogate Molecules
• Pharmacokinetics of Efalizumab
• Clinical Program of Efalizumab: PK/PD Studies, Assessment of Dose, Route, and Regimen
• ■ IV Administration of Efalizumab
• ■ Determination of SC Doses
• ■ SC Administration of Efalizumab
• Mechanistic Modeling Approaches
• Pharmacokinetic Analysis
• Pharmacodynamic Analysis
• Efficacy Analysis
• Model Results
• ■ Population Pharmacokinetics of Monoclonal Antibodies
• Future Perspective
• Self-Assessment Questions
• References
• 8: Genomics, Other “Omic” Technologies, Personalized Medicine, and Additional Biotechnology-Rel
• Introduction
• An Introduction to “Omic” Technologies
• ■ Genomics
• Structural Genomics and the Human Genome Project
• Next-Generation Genome Sequencing (NGS) and the $1,000 Genome
• Functional Genomics and Comparative Genomics
• ■ “Omic”-Enabling Technology: Bioinformatics
• ■ Transcriptomics
• ■ Proteomics, Structural Proteomics, and Functional Proteomics
• ■ “Omic”-Enabling Technology: Microarrays
• ■ “Omic”-Enabled Technology: Brief Introduction to Biomarkers
• ■ Metabonomics and Metabolomics
• ■ Pharmacogenetics and Pharmacogenomics
• Single-Nucleotide Polymorphisms (SNPs)
• Pharmacogenetics Versus Pharmacogenomics
• Genome-Wide Association Studies (GWAS)
• ■ On the Path to Personalized Medicine: A Brief Introduction
• Human Genomic Variation Affecting Drug Pharmacokinetics
• Human Genomic Variation Affecting Drug Pharmacodynamics
• Value of Personalized Medicine in Disease
• Challenges in Personalized Medicine
• Epigenetics and Epigenomics
• ■ Toxicogenomics
• ■ Glycomics and Glycobiology
• Glycosylation and Medicine
• ■ Lipidomics
• ■ Nutrigenomics
• ■ Other “Omic” Technologies
• ■ “Omics” Integrating Technology: Systems Biology
• Transgenic Animals and Plants in Drug Discovery, Development, and Production
• ■ Transgenic Animals
• Production of Transgenic Animals by DNA Microinjection and Random Gene Addition
• Production of Transgenic Animals by Retroviral Infection
• Production of Transgenic Animals by Homologous Recombination in Embryonic Stem Cells Following Micro
• ■ Transgenic Plants
• Biopharmaceutical Protein Production in Transgenic Animals and Plants: “Biopharming”
• ■ Xenotransplantation: Transplantable Transgenic Animal Organs
• ■ Knockout Mice
• Site-Directed Mutagenesis
• Synthetic Biology
• Biotechnology and Drug Discovery
• ■ Screening and Synthesis
• Advances in Screening: High-Throughput Screening (HTS)
• High-Throughput Chemistry: Combinatorial Chemistry and Multiple Parallel Synthesis
• ■ Chemical Genomics
• Conclusion
• Self-Assessment Questions
• References
• 9: Dispensing Biotechnology Products: Handling, Professional Education, and Product Information
• Introduction
• Pharmacist Readiness
• ■ Types of Information Needed by Pharmacists
• ■ Sources of Information for Pharmacists
• ■ The Pharmacist and Handling of Biotech Drugs
• Storage
• ■ Temperature Requirements
• ■ Storage in Dosing and Administration Devices
• ■ Storage in IV Solutions
• ■ Light Protection
• Handling
• ■ Mixing and Shaking
• ■ Travel Requirements
• Preparation
• Administration
• ■ Routes of Administration
• ■ Filtration
• ■ Flushing Solutions
• ■ Prophylaxis to Prevent Infusion Reactions
• Biosimilars: Almost to Market
• Outpatient/Home Care Issues
• ■ Patient Assessment and Education
• ■ Monitoring
• Reimbursement
• Educational Materials
• ■ Educational Materials for Health Professionals
• ■ Educational Materials for Patients
• ■ The Internet and Biotech Information
• Concluding Remarks
• Self-Assessment Questions
• References
• Further Reading
• 10: Economic Considerations in Medical Biotechnology
• Introduction
• The Value of a New Medical Technology
• An Overview of Economic Analysis for New Technologies
• Pharmacoeconomics
• ■ Importance of Pharmacoeconomics
• ■ Understanding Costs
• Direct Costs
• Indirect Costs
• Intangible Costs
• Opportunity Costs
• Understanding Pharmacoeconomic Methods
• ■ Cost of Illness
• ■ Cost-Minimization Analysis
• ■ Cost-Benefit Analysis
• ■ Cost-Effectiveness Analysis (CEA)
• ■ Cost-Utility Analysis (CUA)
• Conclusions
• References
• Further Reading
• 11: Regulatory Framework for Biosimilars
• Introduction
• Background
• Regulatory Framework in the USA
• „ Scale-Up and Postapproval Changes (SUPAC) Concept and Comparability
• Box 11.1 ■ Key Points of the FDA Guidance on Comparability .
• „ Biosimilars and Drug Product Approval
• Box 11.2 ■ FDA Routes for Biosimilars .
• „ Guidance Documents on Biosimilars
• „ Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
• „ Characterization
• „ Clinical Studies
• EMA Regulatory Framework
• „ Immunogenicity (Related to Overarching EMA Document)
• „ Status of Biosimilars in the EU
• The Challenge and the Future
• Self-Assessment Questions
• References
• 12: Insulin
• Introduction
• Chemical Description
• Pharmacology and Formulations
• ■ Regular and Rapid-Acting Soluble Preparations
• ■ Ultrarapid Initiatives
• ■ Intermediate-Acting Insulin Preparations
• ■ Long-Acting Insulin Formulations
• ■ Concentrated Insulin Formulations
• Pharmaceutical Concerns
• ■ Chemical Stability of Insulin Formulations
• ■ Physical Stability of Insulin formulations
• Clinical and Practice Aspects
• ■ Vial Presentations
• ■ Injection Devices
• ■ Continuous Subcutaneous Insulin Infusion: External Pumps
• ■ Noninvasive Delivery
• ■ Storage
• ■ Usage
• Resuspension
• Dosing
• Extemporaneous Mixing
• Self-Assessment Questions
• References
• Recommended Reading
• 13: Follicle-Stimulating Hormone
• Introduction
• FSH Is a Glycoprotein Hormone
• Production of Recombinant FSH
• Description of Recombinant FSH
• „ Structural Characteristics
• „ Biological Properties of Recombinant FSH Isohormones
• „ Pharmacokinetic Behavior of Recombinant FSH Isohormones
• Pharmaceutical Formulations
• Clinical Aspects
• A Newly Developed FSH Analog
• References
• Further Reading
• 14: Human Growth Hormone
• Introduction
• hGH Structure and Isohormones
• Pharmacology
• ■ Growth Hormone Secretion and Regulation
• ■ Growth Hormone Biologic Actions
• ■ hGH Receptor and Binding Proteins
• ■ Molecular Endocrinology and Signal Transduction
• ■ Dosing Schedules and Routes
• ■ Pharmacokinetics and Metabolism
• Protein Manufacture, Formulation, and Stability
• Clinical Usage
• ■ Growth Hormone Deficiency (GHD)
• ■ Idiopathic Short Stature (ISS)
• ■ Turner Syndrome (TS)
• ■ Prader-Willi Syndrome (PWS)
• ■ Small for Gestational Age (SGA)
• ■ Chronic Renal Insufficiency (CRI)/Chronic Kidney Disease (CKD)
• ■ Noonan Syndrome
• ■ Short Stature Homeobox-Containing Gene (SHOX)
• ■ Growth Hormone Deficient Adults
• ■ Clinical Malnutrition and Wasting Syndromes
• ■ Other Conditions Under Investigation
• ■ Safety Concerns
• Concluding Remarks
• Self-Assessment Questions
• References
• Further Reading
• 15: Recombinant Coagulation Factors and Thrombolytic Agents
• Introduction
• Factor VIII
• „ Structure
• „ Pharmacology
• Recombinant Factor VIII
• „ Pharmaceutical Considerations
• „ Clinical Usage
• Safety
• Factor VIIa
• „ Structure
• „ Pharmacology
• Recombinant Factor VIIa
• „ Pharmacokinetics and Pharmacodynamics
• „ Pharmaceutical Considerations
• „ Clinical Usage
• Safety
• „ Recent Developments
• Factor IX
• Recombinant Coagulation Factor IX
• „ Pharmacology
• „ Pharmaceutical Considerations
• „ Clinical Usage
• Safety
• „ Recent Developments
• Factor XIII
• Recombinant Coagulation Factor XIII
• „ Clinical Usage
• Recombinant Thrombolytic Agents
• „ Tissue-Type Plasminogen Activator
• „ Structure
• First-Generation Recombinant Thrombolytic Agents: Recombinant t-PA (rt-PA)
• „ Pharmacokinetics of rt-PA
• „ Pharmaceutical Considerations
• „ Clinical Usage
• Safety Concerns
• Second-Generation Recombinant Thrombolytic Agents
• „ Reteplase
• „ Pharmacology
• „ Pharmaceutical Considerations
• „ Clinical Usage
• Safety Concerns
• „ Tenecteplase
• „ Pharmacology
• „ Pharmaceutical Considerations
• „ Clinical Usage
• Safety Concerns
• „ Lanoteplase
• Conclusions
• Self-Assessment Questions
• References
• 16: Recombinant Human Deoxyribonuclease I
• Introduction
• „ Historical Perspective and Rationale
• Protein Chemistry, Enzymology, and Structure
• Pharmacology
• „ In Vitro Activity in CF Sputum
• „ In Vivo Activity in CF Sputum
• „ Pharmacokinetics and Metabolism
• Protein Manufacturing and Formulation
• Drug Delivery
• Clinical Use
• „ Indication and Clinical Dosage
• „ Cystic Fibrosis
• „ Non-cystic Fibrosis Respiratory Disease
• „ Other Medical Conditions
• „ Safety
• Summary
• Self-Assessment Questions
• References
• 17: Monoclonal Antibodies in Cancer
• Introduction
• Classes of Monoclonal Antibodies: CD Antigens
• ■ Alemtuzumab
• Pharmacology and Pharmacokinetics
• Indications and Clinical Efficacy
• Safety
• ■ Gemtuzumab
• Pharmacology and Pharmacokinetics
• Clinical Considerations
• ■ Rituximab, Yttrium-90 ( 90 Y) Ibritumomab Tiuxetan, Iodine-131 ( 131 I) Tositumomab
• Pharmacology and Pharmacokinetics
• Indications and Clinical Efficacy
• Safety
• Radioimmunotherapy
• ■ Brentuximab Vedotin
• Pharmacology and Pharmacokinetics
• Indications and Clinical Efficacy
• Safety
• Classes of Monoclonal Antibodies: Vascular Endothelial Growth Factor (VEGF) Inhibitors
• ■ Bevacizumab
• Pharmacology and Pharmacokinetics
• Indications and Clinical Efficacy
• Safety
• Classes of Monoclonal Antibodies: Endothelial Growth Factor Receptor (EGFR) Inhibitors
• ■ Trastuzumab
• Pharmacology and Pharmacokinetics
• Indications and Clinical Efficacy
• Safety
• ■ Pertuzumab
• Pharmacology and Pharmacokinetics
• Indications and Clinical Efficacy
• Safety
• ■ Cetuximab
• Pharmacology and Pharmacokinetics
• Indications and Clinical Efficacy
• Safety
• ■ Panitumumab
• Pharmacology and Pharmacokinetics
• Indications and Clinical Efficacy
• Safety
• Classes of Monoclonal Antibodies: Antihuman Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4)
• ■ Ipilimumab
• Pharmacology and Pharmacokinetics
• Indications and Clinical Efficacy
• Safety
• Classes of Monoclonal Antibodies: Receptor Activator of Nuclear Factor Kappa Beta Ligand Inhibitor
• ■ Denosumab
• Pharmacology and Pharmacokinetics
• Indications and Clinical Efficacy
• Safety
• Conclusion
• Self-Assessment Questions
• References
• 18: Hematopoietic Growth Factors: Focus on Erythropoiesis-Stimulating Agents
• Introduction
• Erythropoiesis-Stimulating Agents
• ■ Regulation of Erythropoietin
• ■ Pharmacokinetics
• Absorption
• Bioavailability
• Distribution
• Elimination
• ■ Pharmacodynamics
• ■ Indications for Cancer Patients and Potential Adverse Events
• Myeloid Hematopoietic Growth Factors
• ■ Granulocyte Colony-Stimulating Factor (G-CSF)
• ■ Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and Stem Cell Factor (SCF)
• ■ Megakaryocyte Hematopoietic Growth Factors
• Self-Assessment Questions
• References
• 19: Monoclonal Antibodies in Solid Organ Transplantation
• Introduction
• Immunologic Targets: Rational Development/Use of Monoclonal Antibodies in Organ Transplant
• ■ Monoclonal Antibodies Administered Pre-transplant
• ■ Monoclonal Antibodies Administered at the Time of Transplant
• ■ Monoclonal Antibodies Administered Following Transplant
• Specific Agents Used in Solid Organ Transplant
• ■ Muromonab
• ■ Interleukin-2 Receptor Antagonists
• Daclizumab
• Basiliximab
• ■ Alemtuzumab
• ■ Rituximab
• ■ Eculizumab
• ■ Belatacept
• Conclusion
• Self-Assessment Questions
• References
• 20: Monoclonal Antibodies and Antibody-Based Biotherapeutics in Inflammatory Diseases
• Introduction
• Arthritides
• ■ Abatacept
• ■ Adalimumab
• ■ Certolizumab Pegol
• ■ Etanercept
• ■ Golimumab
• ■ Infliximab
• ■ Rituximab
• ■ Tocilizumab
• Systemic Lupus Erythematosus
• ■ Belimumab
• Psoriasis
• ■ Alefacept
• ■ Anti-TNFα Antagonists (Adalimumab, Etanercept, Infliximab)
• ■ Ustekinumab
• Inflammatory Bowel Disease
• ■ Adalimumab
• ■ Certolizumab Pegol
• ■ Infliximab
• ■ Natalizumab
• Allergic Asthma
• ■ Omalizumab
• Multiple Sclerosis
• ■ Natalizumab
• Cryopyrin-Associated Periodic Syndromes
• ■ Canakinumab
• ■ Rilonacept
• Conclusion
• Self-Assessment Questions
• References
• 21: Interferons and Interleukins
• Introduction
• Interferons: Nomenclature and Functions
• Interleukins: Nomenclature and Functions
• „ Interleukin-1 Family
• „ Interleukin-1
• „ Interleukin-1Ra
• „ Interleukin-18
• „ Interleukin-33
• „ Interleukin-36A, B, and G
• „ Interleukin-36RN
• „ Interleukin-37
• „ Interleukin-38
• „ Interleukin-2 Family
• „ Interleukin-2
• „ Interleukin-4
• „ Interleukin-7
• „ Interleukin-9
• „ Interleukin-15
• „ Interleukin-21
• „ Interleukin-10 Family
• „ Interleukin-10
• „ Interleukin-19
• „ Interleukin-20
• „ Interleukin-22
• „ Interleukin-24
• „ Interleukin-26
• „ Interleukin-28A and B and Interleukin-29
• „ Interleukin-12 Family
• „ Interleukin-12
• „ Interleukin-23
• „ Interleukin-27
• „ Interleukin-35
• „ Interleukin-17 Family
• „ Interleukin-25
• „ Hematopoietin Family
• „ Interleukin-3
• „ Interleukin-5
• „ Interleukin-6
• „ Interleukin-11
• „ Interleukin-13
• Others Not (Yet) Assigned to a Family
• „ Interleukin-8
• „ Interleukin-16
• „ Interleukin-31
• „ Interleukin-32
• „ Interleukin-34
• Therapeutic Use of Recombinant Interferons
• „ IFN-α Therapeutics
• „ IFN-β Therapeutics
• „ IFN-γ Therapeutics
• Therapeutic Use of Recombinant Interleukins
• „ Aldesleukin
• „ Oprelvekin
• „ Anakinra
• PEGylated Interferons and Interleukins: The Next Generation
• Outlook and Conclusions
• Self-Assessment Questions
• References
• Further Reading
• Interferons
• Interleukins
• PEGylation
• 22: Vaccines
• Introduction
• Immunological Principles
• ■ Introduction
• ■ Active Immunization: Generation of an Immune Response
• ■ Innate Response
• ■ Activation and Migration
• ■ Antigen Presentation and Lymphocyte Activation
• ■ The Adaptive Immune System
• ■ Vaccine Design in Relation with the Immune Response
• ■ Route of Administration
• Classical Vaccines
• ■ Classification
• ■ Live Attenuated Vaccines
• ■ Nonliving Vaccines: Whole Organisms
• ■ Nonliving Vaccines: Subunit Vaccines
• Diphtheria and Tetanus Toxoids
• Acellular Pertussis Vaccines
• Polysaccharide Vaccines
• Modern Vaccine Technologies
• ■ Modern Live Vaccines
• Genetically Attenuated Microorganisms
• Live Vectored Vaccines
• ■ Modern Subunit Vaccines
• Recombinant Protein Vaccines
• Recombinant Peptide Vaccines
• Synthetic Peptide-Based Vaccines
• Nucleic Acid Vaccines
• ■ Reverse Vaccinology
• ■ Therapeutic Vaccines
• Cancer Vaccines
• Vaccines Against Drug Abuse
• ■ Systems Biology and Vaccines
• Pharmaceutical Aspects
• ■ Production
• ■ Formulation
• Adjuvants, Immune Potentiators, and Delivery Systems
• Combination Vaccines
• ■ Characterization
• ■ Storage
• Concluding Remarks
• Self-Assessment Questions
• References
• Further Reading
• 23: Oligonucleotides
• Introduction
• Direct Binding to Non-Nucleic Acids
• ■ Aptamers/Riboswitches
• ■ Stimulating Immune Responses
• Gene Repair and Chromosomal Change
• ■ Triplex Helix-Forming Oligonucleotides
• ■ Antisense-Induced Exon Skipping
• ■ Antisense-Induced Ribonucleoprotein Inhibition
• Interfering with Gene Expression
• ■ Triple Helix-Forming Oligonucleotides
• ■ Transcription Factor Decoys
• ■ Antisense/Ribozymes/External Guide Sequences
• ■ siRNA/miRNA
• Pharmacokinetics of Oligonucleotide-Based Therapeutics
• Improving Oligonucleotide Stability
• Improving Cellular Uptake
• Diagnostic Applications
• Perspectives
• Self-Assessment Questions
• References
• Further Reading
• 24: Gene Therapy
• Introduction
• Vectors for Gene Transfer
• ■ Basic Components of Plasmid (cf.Chap. 1)
• Bacterial Elements
• Transcription Regulatory Elements (TRE)
• Multiple Cloning Site (MCS)
• Untranslated Regions (UTR)
• Introns
• Polyadenylation (polyA) Sequence
• Fusion Tag
• Viral Vectors
• ■ Retrovirus
• Biology
• Suitability of Retroviruses as Vectors for Gene Transfer
• Clinical Use of Retrovirus
• ■ Lentivirus
• Biology
• Suitability of Lentiviruses as Vectors for Gene Transfer
• Clinical Use of Lentiviral Vectors
• ■ Adenovirus
• Biology
• Suitability of Adenoviruses as Vectors for Gene Transfer
• Clinical Use of Adenoviral Vectors
• ■ Adeno-Associated Virus (AAV)
• Biology
• Suitability of Adeno-Associated Viruses for Gene Transfer
• Clinical Use of Adeno-Associated Virus Vectors
• Nonviral Vectors
• ■ Delivery Methods for Nonviral Gene Transfer
• Physical Methods for Gene Transfer
• Cationic Lipids
• Peptides
• Polymers
• ■ Clinical Use of Nonviral Vectors
• Stem-Cell-Based Gene Therapy
• Stem Cell Therapy (cf. Chap. 25)
• Stem Cells as Gene Delivery Vehicles
• Stem Cells as Regenerative Medicine (cf. Chap. 25)
• Disease Targets for Gene Therapy
• Cancer Gene Therapy
• ■ Correction of Genetic Mutations
• ■ Immunotherapy
• ■ Tumors Sensitization
• ■ Gene-Directed Enzyme-Prodrug Therapy
• ■ Oncolytic Viruses (Virotherapy)
• ■ Nonviral Gene Therapy
• Monogenetic Diseases
• Cardiovascular Diseases
• Infectious Diseases
• Neurological Diseases
• Regulatory Issues of Gene Therapy Products
• Concluding Remarks
• Self-Assessment Questions and Answers
• References
• Further Reading
• 25: Stem Cell Technology
• Introduction
• ■ Significance of Stem Cell Technology
• ■ What Is a Stem Cell?
• ■ Adult Stem Cells
• ■ Embryonic Stem Cells
• ■ Maintenance and Differentiation of ES Cells in Culture
• ■ Cell Therapy: The Broader Context
• Immunological Considerations in Cell Therapy
• IPS Cell Technology
• Direct Reprogramming
• Use of Products Derived from Stem Cells in Cell Therapy
• Disease Modeling and Drug Discovery
• Cancer Stem Cells
• Regulatory Issues
• Concluding Remarks
• Self-Assessment Questions
• References
• Index