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Therapeutic Antibody Engineering
Current and Future Advances Driving the Strongest Growth Area in the Pharmaceutical Industry
William R Strohl (Author), Lila M Strohl (Author)
9781907568374, Elsevier Science
Hardback, published 16 October 2012
696 pages
23.3 x 15.6 x 3.7 cm, 1.19 kg
"An excellent balance between readability and depth of material.... The book is well referenced and provides plentiful opportunities to continue subject-specific learing." --mAbs Journal"An excellent book describing many aspects of therapeutic antibody generation and the current market share of these drugs. It is an up-to-date evaluation of their production and clinical utility." --Doody's Reviews
The field of antibody engineering has become a vital and integral part of making new, improved next generation therapeutic monoclonal antibodies, of which there are currently more than 300 in clinical trials across several therapeutic areas. Therapeutic antibody engineering examines all aspects of engineering monoclonal antibodies and analyses the effect that various genetic engineering approaches will have on future candidates. Chapters in the first part of the book provide an introduction to monoclonal antibodies, their discovery and development and the fundamental technologies used in their production. Following chapters cover a number of specific issues relating to different aspects of antibody engineering, including variable chain engineering, targets and mechanisms of action, classes of antibody and the use of antibody fragments, among many other topics. The last part of the book examines development issues, the interaction of human IgGs with non-human systems, and cell line development, before a conclusion looking at future issues affecting the field of therapeutic antibody engineering.
List of figures List of tables List of acronyms, abbreviations, and definitions Foreword Preface About the authors Chapter 1: Introduction to biologics and monoclonal antibodies Abstract: 1.1 Introduction 1.2 Definitions of biologies 1.3 Recombinant protein therapeutics 1.4 MAbs and Fc fusion proteins (FcFPs) 1.5 General anatomy of a therapeutic IgG MAb 1.6 Naming convention for antibodies from different sources Chapter 2: Value proposition for therapeutic monoclonal antibodies and Fc fusion proteins Abstract: 2.1 Overview of discovery and development of therapeutic MAbs and FcFPs 2.2 Market for MAbs and FcFPs 2.3 Currently and recently approved MAbs and FcFPs Chapter 3: Antibody structure–function relationships Abstract: 3.1 Introduction 3.2 Constant region structure/function 3.3 FAb structure/function Chapter 4: Fundamental technologies for antibody engineering Abstract: 4.1 Introduction 4.2 Hybridoma technology – the gateway for therapeutic monoclonal antibodies 4.3 Key recombinant DNA technologies 4.4 Generation of chimeric antibodies 4.5 Display technologies 4.6 Maturity timelines for biologies technologies Chapter 5: Sources of antibody variable chains Abstract: 5.1 Human antibody gene organization 5.2 Antibody gene rearrangement and diversity in vivo 5.3 Sources of antibody diversity 5.4 Class-switch recombination 5.5 Human variable gene usage 5.6 Variable region selection 5.7 Variable genes from non-human species 5.8 Use of variable genes from humans Chapter 6: Variable chain engineering – humanization and optimization approaches Abstract: 6.1 Introduction 6.2 Chimerization 6.3 Humanization 6.4 Affinity optimization Chapter 7: Antibody interactions with the immune system Abstract: 7.1 Introduction 7.2 Human Fc? receptors 7.3 FcRn and its effect on MAb and FcFP half-life 7.4 Other Fc receptors of importance 7.5 Complement activation Chapter 8: Monoclonal antibody targets and mechanisms of action Abstract: 8.1 Properties of antibody targets 8.2 Antibody mechanisms of action 8.3 CD20 – example of a target for which multiple MOAs apply Chapter 9: Therapeutic antibody classes Abstract: 9.1 Human antibody overview 9.2 Human IgG isotypes 9.3 IgM 9.4 IgA Chapter 10: Antibody Fc engineering for optimal antibody performance Abstract: 10.1 Antibody engineering for decreased or increased effector function 10.2 Current marketed MAbs and clinical candidates with modified Fc 10.3 The effect of human Fc polymorphisms on disease and therapeutic index 10.4 Fc engineering of IgGs to increase effector function 10.5 Fc engineering for silenced effector function 10.6 Fc?RIIb-dependent suppression of immune response 10.7 Antibody engineering for modulation of pharmacokinetics 10.8 Tissue targeting Chapter 11: IgG glycans and glyco-engineering Abstract: 11.1 Introduction to Fc glycosylation 11.2 Non-glycosylated IgGs for lowered effector function 11.3 Low- or non-fucosylated oligosaccharides result in higher ADCC 11.4 Non-sialylated IgG glycans result in increased ADCC 11.5 Sialylated IgG glycans may result in immunosuppressive effects 11.6 High-mannose glycoforms 11.7 FAb glycosylation Chapter 12: Antibody fragments as therapeutics Abstract: 12.1 Introduction to antibody fragments and alternative formats 12.2 FAb and scFv antibody fragments 12.3 Domain antibodies, including nanobodies, IgNARs, and nanoantibodies 12.4 Antibody size and tissue distribution 12.5 Strategies for half-life extension of antibody fragments 12.5.2 PEGylation Chapter 13: Multiple antibody and multi-specificity approaches Abstract: 13.1 Introduction 13.2 Serum therapy 13.3 IVIG 13.4 Multi-antibody approaches 13.5 Bispecific antibodies based on IgGs 13.6 Bispecific antibody fragments Chapter 14: FcFPs and similar constructs using Fc Abstract: 14.1 Introduction 14.2 Receptor-FcFPs 14.3 Traps: multi-ligand binding domains of different receptor chains fused to Fc region 14.4 Soluble protein FcFPs 14.5 Antibody fragment – Fc fusion proteins 14.6 Fc peptide fusions as receptor agonist therapeutics 14.7 Other FcFP structures 14.8 Issues to consider with FcFPs Chapter 15: Antibody-drug conjugates Abstract: 15.1 Introduction to antibody-drug conjugates 15.2 Overview and anatomy of a typical ADC 15.3 ADC antibodies and targets 15.4 ADC chemical “warheads? 15.5 ADC linkers 15.6 Issues, limitations, and design of ADCs 15.7 Radioimmunoconjugates 15.8 Protein immunotoxins 15.9 ADEPT 15.10 Other ADC-like approaches Chapter 16: Development issues: antibody stability, developability, immunogenicity, and comparability Abstract: 16.1 Introduction 16.2 Aggregation 16.3 Lack of desired solubility 16.4 Fragmentation 16.5 Post-translational amino acid residue modifications 16.6 Instability and isomerization of disulfide bonds 16.7 Stability at low pH 16.8 Glycosylation issues 16.9 Immunogenicity 16.10 Biocomparability Chapter 17: Interactions of human IgGs with non-human systems Abstract: 17.1 Introduction 17.2 Non-human primate IgGs and Fc? receptors 17.3 Mouse IgGs and Fc? receptors Chapter 18: Cell line development Abstract: 18.1 Introduction 18.2 Process summary 18.3 Key issues in cell line development 18.4 Choice of cell line 18.5 Mammalian cell lines 18.6 Microbial cells 18.7 Multiple cell lines in single batches 18.8 Gene and vector optimization and selectable markers 18.9 Other industry trends Chapter 19: Issues facing therapeutic monoclonal antibodiesfor the future Abstract: 19.1 Introduction to the future state 19.2 Commoditization of the core underlying technologies 19.3 Impact of follow-on MAbs and FcFPs 19.4 Competition 19.5 The continued need for, and limitation of, novel pre-clinically validated targets 19.6 Payor pressure 19.7 Pipeline in a product concept 19.8 Companion diagnostics and patient segmentation 19.9 Treatment with multiple antibodies and bispecific antibodies 19.10 MAb and FcFP conjugates 19.11 Biopharma in 2020 – the focus on BRIC 19.12 SWOT analysis of therapeutic MAbs and FcFPs 19.13 Epilogue Useful public websites related to antibody engineering References Index
