Therapeutic Antibody Engineering

Therapeutic Antibody Engineering

Current and Future Advances Driving the Strongest Growth Area in the Pharmaceutical Industry

1st Edition - October 16, 2012

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  • Authors: William Strohl, Lila Strohl
  • Hardcover ISBN: 9781907568374
  • eBook ISBN: 9781908818096

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Description

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.

Key Features

  • Goes beyond the standard engineering issues covered by most books and delves into structure-function relationships
  • Integration of knowledge across all areas of antibody engineering, development, and marketing
  • Discusses how current and future genetic engineering of cell lines will pave the way for much higher productivity

Readership

Microbiologists, biochemists, oncologists;

Table of Contents

  • 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 Fcγ 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 FcγRIIb-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 Fcγ receptors

    17.3 Mouse IgGs and Fcγ 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

Product details

  • No. of pages: 696
  • Language: English
  • Copyright: © Woodhead Publishing 2012
  • Published: October 16, 2012
  • Imprint: Woodhead Publishing
  • Hardcover ISBN: 9781907568374
  • eBook ISBN: 9781908818096

About the Authors

William Strohl

Dr William R. Strohl is Vice President of Biologics Research at Janssen R&D Biotechnology Center of Excellence, and was previously a leader in Merck’s efforts to discover therapeutic monoclonal antibodies, as well as in-licensing of therapeutic targets and technologies associated with monoclonal antibodies. He has over 100 publications and several patents to his credit, and has edited two books.

Affiliations and Expertise

Johnson & Johnson Biotechnology Center of Excellence

Lila Strohl

Affiliations and Expertise

Medical Illustrator, USA

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