Therapeutic Antibody Engineering : Current and Future Advances Driving the Strongest Growth Area in the Pharmaceutical Industry

ISBN-13: 9781907568374 / Angielski / Twarda / 2012 / 696 str.

William R. Strohl; Lila Strohl

Opis

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.

• 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

Recenzje

"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

Spis treści

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 structureâ?"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 â?" 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

O autorze

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.