Therapeutic Antibody Engineering

<p>List of figures</p> <p>List of tables</p> <p>List of acronyms, abbreviations, and definitions</p> <p>Foreword</p> <p>Preface</p> <p>About the authors</p> <p>Chapter 1: Introduction to biologics and monoclonal antibodies</p> <p>Abstract:</p> <p>1.1 Introduction</p> <p>1.2 Definitions of biologies</p> <p>1.3 Recombinant protein therapeutics</p> <p>1.4 MAbs and Fc fusion proteins (FcFPs)</p> <p>1.5 General anatomy of a therapeutic IgG MAb</p> <p>1.6 Naming convention for antibodies from different sources</p> <p>Chapter 2: Value proposition for therapeutic monoclonal antibodies and Fc fusion proteins</p> <p>Abstract:</p> <p>2.1 Overview of discovery and development of therapeutic MAbs and FcFPs</p> <p>2.2 Market for MAbs and FcFPs</p> <p>2.3 Currently and recently approved MAbs and FcFPs</p> <p>Chapter 3: Antibody structure–function relationships</p> <p>Abstract:</p> <p>3.1 Introduction</p> <p>3.2 Constant region structure/function</p> <p>3.3 FAb structure/function</p> <p>Chapter 4: Fundamental technologies for antibody engineering</p> <p>Abstract:</p> <p>4.1 Introduction</p> <p>4.2 Hybridoma technology – the gateway for therapeutic monoclonal antibodies</p> <p>4.3 Key recombinant DNA technologies</p> <p>4.4 Generation of chimeric antibodies</p> <p>4.5 Display technologies</p> <p>4.6 Maturity timelines for biologies technologies</p> <p>Chapter 5: Sources of antibody variable chains</p> <p>Abstract:</p> <p>5.1 Human antibody gene organization</p> <p>5.2 Antibody gene rearrangement and diversity in vivo</p> <p>5.3 Sources of antibody diversity</p> <p>5.4 Class-switch recombination</p> <p>5.5 Human variable gene usage</p> <p>5.6 Variable region selection</p> <p>5.7 Variable genes from non-human species</p> <p>5.8 Use of variable genes from humans</p> <p>Chapter 6: Variable chain engineering – humanization and optimization approaches</p> <p>Abstract:</p> <p>6.1 Introduction</p> <p>6.2 Chimerization</p> <p>6.3 Humanization</p> <p>6.4 Affinity optimization</p> <p>Chapter 7: Antibody interactions with the immune system</p> <p>Abstract:</p> <p>7.1 Introduction</p> <p>7.2 Human Fcγ receptors</p> <p>7.3 FcRn and its effect on MAb and FcFP half-life</p> <p>7.4 Other Fc receptors of importance</p> <p>7.5 Complement activation</p> <p>Chapter 8: Monoclonal antibody targets and mechanisms of action</p> <p>Abstract:</p> <p>8.1 Properties of antibody targets</p> <p>8.2 Antibody mechanisms of action</p> <p>8.3 CD20 – example of a target for which multiple MOAs apply</p> <p>Chapter 9: Therapeutic antibody classes</p> <p>Abstract:</p> <p>9.1 Human antibody overview</p> <p>9.2 Human IgG isotypes</p> <p>9.3 IgM</p> <p>9.4 IgA</p> <p>Chapter 10: Antibody Fc engineering for optimal antibody performance</p> <p>Abstract:</p> <p>10.1 Antibody engineering for decreased or increased effector function</p> <p>10.2 Current marketed MAbs and clinical candidates with modified Fc</p> <p>10.3 The effect of human Fc polymorphisms on disease and therapeutic index</p> <p>10.4 Fc engineering of IgGs to increase effector function</p> <p>10.5 Fc engineering for silenced effector function</p> <p>10.6 FcγRIIb-dependent suppression of immune response</p> <p>10.7 Antibody engineering for modulation of pharmacokinetics</p> <p>10.8 Tissue targeting</p> <p>Chapter 11: IgG glycans and glyco-engineering</p> <p>Abstract:</p> <p>11.1 Introduction to Fc glycosylation</p> <p>11.2 Non-glycosylated IgGs for lowered effector function</p> <p>11.3 Low- or non-fucosylated oligosaccharides result in higher ADCC</p> <p>11.4 Non-sialylated IgG glycans result in increased ADCC</p> <p>11.5 Sialylated IgG glycans may result in immunosuppressive effects</p> <p>11.6 High-mannose glycoforms</p> <p>11.7 FAb glycosylation</p> <p>Chapter 12: Antibody fragments as therapeutics</p> <p>Abstract:</p> <p>12.1 Introduction to antibody fragments and alternative formats</p> <p>12.2 FAb and scFv antibody fragments</p> <p>12.3 Domain antibodies, including nanobodies, IgNARs, and nanoantibodies</p> <p>12.4 Antibody size and tissue distribution</p> <p>12.5 Strategies for half-life extension of antibody fragments</p> <p>12.5.2 PEGylation</p> <p>Chapter 13: Multiple antibody and multi-specificity approaches</p> <p>Abstract:</p> <p>13.1 Introduction</p> <p>13.2 Serum therapy</p> <p>13.3 IVIG</p> <p>13.4 Multi-antibody approaches</p> <p>13.5 Bispecific antibodies based on IgGs</p> <p>13.6 Bispecific antibody fragments</p> <p>Chapter 14: FcFPs and similar constructs using Fc</p> <p>Abstract:</p> <p>14.1 Introduction</p> <p>14.2 Receptor-FcFPs</p> <p>14.3 Traps: multi-ligand binding domains of different receptor chains fused to Fc region</p> <p>14.4 Soluble protein FcFPs</p> <p>14.5 Antibody fragment – Fc fusion proteins</p> <p>14.6 Fc peptide fusions as receptor agonist therapeutics</p> <p>14.7 Other FcFP structures</p> <p>14.8 Issues to consider with FcFPs</p> <p>Chapter 15: Antibody-drug conjugates</p> <p>Abstract:</p> <p>15.1 Introduction to antibody-drug conjugates</p> <p>15.2 Overview and anatomy of a typical ADC</p> <p>15.3 ADC antibodies and targets</p> <p>15.4 ADC chemical “warheads”</p> <p>15.5 ADC linkers</p> <p>15.6 Issues, limitations, and design of ADCs</p> <p>15.7 Radioimmunoconjugates</p> <p>15.8 Protein immunotoxins</p> <p>15.9 ADEPT</p> <p>15.10 Other ADC-like approaches</p> <p>Chapter 16: Development issues: antibody stability, developability, immunogenicity, and comparability</p> <p>Abstract:</p> <p>16.1 Introduction</p> <p>16.2 Aggregation</p> <p>16.3 Lack of desired solubility</p> <p>16.4 Fragmentation</p> <p>16.5 Post-translational amino acid residue modifications</p> <p>16.6 Instability and isomerization of disulfide bonds</p> <p>16.7 Stability at low pH</p> <p>16.8 Glycosylation issues</p> <p>16.9 Immunogenicity</p> <p>16.10 Biocomparability</p> <p>Chapter 17: Interactions of human IgGs with non-human systems</p> <p>Abstract:</p> <p>17.1 Introduction</p> <p>17.2 Non-human primate IgGs and Fcγ receptors</p> <p>17.3 Mouse IgGs and Fcγ receptors</p> <p>Chapter 18: Cell line development</p> <p>Abstract:</p> <p>18.1 Introduction</p> <p>18.2 Process summary</p> <p>18.3 Key issues in cell line development</p> <p>18.4 Choice of cell line</p> <p>18.5 Mammalian cell lines</p> <p>18.6 Microbial cells</p> <p>18.7 Multiple cell lines in single batches</p> <p>18.8 Gene and vector optimization and selectable markers</p> <p>18.9 Other industry trends</p> <p>Chapter 19: Issues facing therapeutic monoclonal antibodiesfor the future</p> <p>Abstract:</p> <p>19.1 Introduction to the future state</p> <p>19.2 Commoditization of the core underlying technologies</p> <p>19.3 Impact of follow-on MAbs and FcFPs</p> <p>19.4 Competition</p> <p>19.5 The continued need for, and limitation of, novel pre-clinically validated targets</p> <p>19.6 Payor pressure</p> <p>19.7 Pipeline in a product concept</p> <p>19.8 Companion diagnostics and patient segmentation</p> <p>19.9 Treatment with multiple antibodies and bispecific antibodies</p> <p>19.10 MAb and FcFP conjugates</p> <p>19.11 Biopharma in 2020 – the focus on BRIC</p> <p>19.12 SWOT analysis of therapeutic MAbs and FcFPs</p> <p>19.13 Epilogue</p> <p>Useful public websites related to antibody engineering</p> <p>References</p> <p>Index</p>