Biotherapeutics: Recent Developments using Chemical and Molecular Biology

330 Pages·2013·4.89 MB·English

by  David Fox, Lyn H Jones, Andrew J McKnight, Peter H Seeberger, Sterghios A Moschos, Christine Power, Edmund Graziani, Rob Liskamp, Ben Davis, Kim Janda, Duncan McGregor, Christian Heinis, Pallavi Tawde, Hilde Revets, John Chaddock, David A Spiegel, Henrik

Biotherapeutics
Recent Developments using Chemical and Molecular Biology
P. ublishedo n0 6S eptember2 013o nh ttp://pubs.rsc.orgd | oi:10.1039/9781849737159-FP001
RSC Drug Discovery Series
Editor-in-Chief:
Professor David Thurston, King’s College, London, UK
Series Editors:
Dr David Fox, Vulpine Science and Learning, UK
Professor Ana Martinez, Medicinal Chemistry Institute-CSIC, Madrid, Spain
Professor David Rotella, Montclair State University, USA
Advisor to the Board:
Professor Robin Ganellin, University College London, UK
Titles in the Series:
1: Metabolism, Pharmacokinetics and 21: Designing Multi-Target Drugs
Toxicity of Functional Groups 22: Nanostructured Biomaterials for
2: Emerging Drugs and Targets for Overcoming Biological Barriers
Alzheimer’s Disease; Volume 1 23: Physico-Chemical and
3: Emerging Drugs and Targets for Computational Approaches to
Alzheimer’s Disease; Volume 2 Drug Discovery
4: Accounts in Drug Discovery 24: Biomarkers for Traumatic Brain
5: New Frontiers in Chemical Biology Injury
6: Animal Models for 25: Drug Discovery from Natural
Neurodegenerative Disease Products
7: Neurodegeneration 26: Anti-Inflammatory Drug Discovery
8: G Protein-Coupled Receptors 27: New Therapeutic Strategies for
9: Pharmaceutical Process Type 2 Diabetes: Small Molecules
Development 28: Drug Discovery for Psychiatric
10: Extracellular and Intracellular Disorders
Signaling 29: Organic Chemistry of Drug
11: New Synthetic Technologies in Degradation
Medicinal Chemistry 30: Computational Approaches to
12: New Horizons in Predictive Nuclear Receptors
Toxicology 31: Traditional Chinese Medicine
13: Drug Design Strategies: 32: Successful Strategies for the
Quantitative Approaches Discovery of Antiviral Drugs
14: Neglected Diseases and Drug 33: Comprehensive Biomarker
Discovery Discovery and Validation
15: Biomedical Imaging for Clinical Application
16: Pharmaceutical Salts and Cocrystals 34: Emerging Drugs and Targets for
17: Polyamine Drug Discovery Parkinson’s Disease
18: Proteinases as Drug Targets 35: Pain Therapeutics; Current and
19: Kinase Drug Discovery Future Treatment Paradigms
20: Drug Design Strategies: 36: Biotherapeutics: Recent
Computational Techniques Developments using Chemical and
and Applications Molecular Biology
How to obtain future titles on publication:
A standing order plan is available for this series. A standing order will bring
delivery of each new volume immediately on publication.
For further information please contact:
Book Sales Department, Royal Society of Chemistry, Thomas Graham House,
Science Park, Milton Road, Cambridge, CB4 0WF, UK
Telephone: [phone], Fax: [phone],
Email:
Biotherapeutics
Recent Developments using Chemical and
Molecular Biology
Edited by
Lyn H. Jones
Pfizer R&D
WorldWide Medicinal Chemistry
Cambridge, MA
USA
Email:
RSC Drug Discovery Series No. 36
ISBN: 978-1-84973-601-5
ISSN: 2041-3203
A catalogue record for this book is available from the British Library
r The Royal Society of Chemistry 2013
All rights reserved
Apart from fair dealing for the purposes of research for non-commercial purposes or for
private study, criticism or review, as permitted under the Copyright, Designs and Patents
Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may not
be reproduced, stored or transmitted, in any form or by any means, without the prior
permission in writing of The Royal Society of Chemistry or the copyright owner, or in
the case of reproduction in accordance with the terms of licences issued by the Copyright
Licensing Agency in the UK, or in accordance with the terms of the licences issued by
the appropriate Reproduction Rights Organization outside the UK. Enquiries concerning
reproduction outside the terms stated here should be sent to The Royal Society of
Chemistry at the address printed on this page.
The RSC is not responsible for individual opinions expressed in this work.
Published by The Royal Society of Chemistry,
Thomas Graham House, Science Park, Milton Road,
Cambridge CB4 0WF, UK
Registered Charity Number 207890
For further information see our web site at www.rsc.org
VP. uiebwliO shneldino en0 6S eptember2 013o nh ttp://pubs.rsc.orgd | oi:10.1039/9781849737159-FP001
Preface
Biotherapeutic modalities are often considered beyond the reach of the
medicinal chemist. The language and terminology can differ significantly
between small and large molecule drug discovery, and yet the aims are
essentially the same. We believe chemistry has an essential role in the future
success of this exciting area, and this book was conceived as an attempt to
illustrate the successful partnership of chemical and molecular biology to
enable and advance biotherapeutics (so-called ‘chemologics’).
The design–synthesis–screen–design cycle, an engine for successful small
molecule drug discovery, is not usually a component of biotherapeutic
discovery, yet our challenge to this community is that that need not be the
case – a deeper molecular understanding should be brought to bear in the
biotherapeutics field, such that the empiricism that currently persists can be
addressed. The challenge will be to generate knowledge and apply those
learnings prospectively to avoid making the same mistakes and accelerate our
decision making – the delineation of structure–function or structure–toxicology
relationships will find increasing value in the biotherapeutic space. Small
molecule drug discovery has already evolved past the period of ‘make lots of
stuff, screen lots of stuff, and see what pops out!’ It is neither inspiring nor
cost effective – design strategies are now far more sophisticated, augmented
significantly by advances in biophysical techniques, computational sciences and
the accuracy of predictive in silico tools. Our belief is that these methods will be
harnessed to a greater extent in the advancement of biotherapeutic discovery
and optimization approaches in the future.
This book approaches the huge area of biotherapeutics from the perspective
of improved molecular design, which draws from the synergies between
chemical biology, medicinal chemistry and molecular biology in particular.
Recent developments in these disciplines that have delivered drugs, clinical
candidates or significantly advanced biotherapeutic discovery and design will
RSC Drug Discovery Series No. 36
Biotherapeutics: Recent Developments using Chemical and Molecular Biology
Edited by Lyn H. Jones and Andrew J. McKnight
r The Royal Society of Chemistry 2013
Published by the Royal Society of Chemistry, www.rsc.org
v
P . ehsilbu eS 60 no d etp ebm rr.sbup/:pth no 3102 cs ro. PF-9517379481879/9301.01:iod | g 50
vi Preface
be described. A broad range of modalities are highlighted that will appeal to
those working in a number of biomolecular areas (oligonucleotides, sugars,
proteins and peptides). The chapters, written by an impressive list of world
experts in their respective fields, detail a number of diverse therapeutic
opportunities, including immunopharmacotherapy, optimized fully human or
humanized antibodies, bicyclic peptide phage libraries, synthetic proteins and
vaccines, micro-RNA, bacterial toxins, stabilized cyclotides, antibody–drug
conjugates, peptide epitope mimicry and synthetic immunology.
Additionally, we believe this book will serve as inspiration for the medicinal
chemistry community, particularly when presented with examples of how their
expertise can make considerable impact in the biotherapeutics arena. Much has
been made of the need to chose the ‘best target’ in drug discovery, but as much
emphasis should then be placed on choosing the ‘best modality’, really, our
approach should be ‘modality agnostic’.
Our vision is that all biopharmaceutical chemists, whether in industry or
academia, are equipped with capabilities both in small and large molecule drug
discovery (and as a minimum can speak the language of, and engage in,
‘biotherapies’) and we hope this book will help towards that goal. In some
ways, this book is a call to the traditional small molecule medicinal chemistry
community to ask broader questions of their projects and therapeutic
programmes. At the earliest stage of interest in a biological target we should be
asking ‘what therapeutic modalities shall we apply?’ and both chemists and
biologists are fundamental to the success of those strategic discussions, as well
as the successful prosecution of the programme.
We are extremely grateful to the authors of the chapters in this book. They
have not only described their areas of interest and expertise with great skill, but
they have also shared compelling insights into the future opportunities for
biotherapeutics. We also thank Rosalind Searle and Cara Sutton, RSC
Publishing, for their editorial support and encouragement.
Lyn H. Jones and Andrew J. McKnight
VP. uiebwlis Ohendli noen 06 September 2013 on http://pubs.rsc.org | doi:10.1039/9781849737159-FP005
Contents
Chapter 1 Synthetic Immunology 1
Thihan R. Padukkavidana, Patrick J. MCEnaney and
David A. Spiegel
1.1 Introduction and Scope 1
1.2 Synthetic Ligands for Pattern Recognition Receptors
(PRRs) 2
1.2.1 Synthetic Mimics of TLR Ligands 2
1.2.2 Synthetic NOD Agonists 6
1.2.3 Peroxisome Proliferator-activated Receptor
Gamma 8
1.2.4 C-Type Lectin Receptors (CLRs) 9
1.3 Synthetic Systems for Controlling Cell–Cell
Communication: Cytokine Mimetics 10
1.4 Synthetic Molecules that Modulate the Complement
System 13
1.5 Mimicking and Hijacking Antibody Function 15
1.6 Synthetic Molecules that Modulate T- and B-cell
Responses 17
1.7 Concluding Remarks 22
References 22
Chapter 2 Immunopharmacotherapy for Nicotine Addiction 36
Jonathan W. Lockner and Kim D. Janda
2.1 Introduction 36
2.2 Nicotine and the Body 37
2.3 Nicotine and the Brain 38
2.4 Nicotine and the Immune System 40
RSC Drug Discovery Series No. 36
Biotherapeutics: Recent Developments using Chemical and Molecular Biology
Edited by Lyn H. Jones and Andrew J. McKnight
r The Royal Society of Chemistry 2013
Published by the Royal Society of Chemistry, www.rsc.org
vii
silbuP . eh o d neS 60 tp eebm o 3102 r nth tsbup/:p sr. o.c od | gr 70PF-9517379481879/9301.01:i
viii Contents
2.5 Nicotine and the Antibody 41
2.6 Preclinical Studies of Nicotine
Immunopharmacotherapy 43
2.6.1 Janda 44
2.6.2 Pentel 45
2.6.3 Sanderson 46
2.6.4 Bunce/Bond/Aker 47
2.6.5 Maurer/Bachmann 47
2.6.6 Cerny 48
2.6.7 Svensson/de Villiers 48
2.6.8 Crystal 49
2.7 Clinical Trials of Nicotine Vaccines 49
2.7.1 Cytos Biotechnology AG 50
2.7.2 ImmuLogic/Cantab/Xenova/Celtic Pharma 50
2.7.3 Nabi Biopharmaceuticals/Biota
Pharmaceuticals 51
2.7.4 Chilka Limited 51
2.7.5 Independent Pharmaceutica AB 52
2.7.6 Selecta Biosciences 52
2.7.7 Pfizer Vaccines Ltd 52
2.8 New Directions to Improve Immunogenicity 53
2.8.1 Carrier 54
2.8.2 Delivery Method 54
2.8.3 Adjuvants 55
2.8.4 Hapten Design 56
2.8.5 Caveat: No Nicotine Vaccine Should Be
Viewed as a ‘‘Magic Bullet’’ Cure 57
2.8.6 Miscellany 58
2.9 Conclusions and Future Prospects 59
Acknowledgements 60
References 60
Chapter 3 Carbohydrate Vaccines 68
Benjamin Schumann, Chakkumkal Anish,
Claney L. Pereira and Peter H. Seeberger
3.1 Introduction 68
3.1.1 Cell Surface Glycans as Vaccine Candidates 69
3.1.2 Immunology of Carbohydrate-based Vaccines 72
3.1.3 Production and Manufacture of
Glycoconjugate Vaccines 74
3.1.4 Opportunities and Challenges of Vaccines
Based on Synthetic Oligosaccharides 77
3.2 Chemical Immunology of Glycoconjugate Vaccines 77
3.2.1 Effect of the Glycan on the Immune Response 78
3.2.1.1 Saccharide Length 78
3.2.1.2 Epitope Charge 79
VP. uiebwlis Ohendli noen 06 September 2013 on http://pubs.rsc.org | doi:10.1039/9781849737159-FP007
Contents ix
3.2.1.3 Exposed Epitopes 80
3.2.1.4 Monosaccharide Modifications 82
3.2.2 Effects of Conjugation on the Immune
Response 83
3.2.2.1 Conjugation Chemistry 83
3.2.2.2 Immunogenicity of Linker/Spacer
Constructs 83
3.2.2.3 Antigen Density 83
3.2.2.4 T Cell Epitopes 84
3.2.2.5 Carrier Priming and Carrier-Induced
Epitope Suppression 85
3.3 Novel Developments in Vaccine Design 86
3.3.1 Multicomponent Vaccines 86
3.3.2 Novel Carrier Platforms 87
3.3.3 Rational Vaccine Design 88
3.4 Conclusions 89
Acknowledgements 90
References 90
Chapter 4 Generation and Maturation of Therapeutic Antibodies via
In Vitro Somatic Hypermutation 105
David J. King
4.1 Antibodies as Therapeutic Agents 105
4.2 Approaches to the Generation of Therapeutic
Antibodies 106
4.2.1 Recovery of Antibodies from In Vivo Sources 108
4.2.2 Recovery of Antibodies from In Vitro Sources 110
4.3 Mammalian Cell Display 113
4.4 Somatic Hypermutation (SHM) 117
4.5 Combining Mammalian Cell Display with In Vitro
SHM 119
References 123
Chapter 5 Synthetic Protein Biologics 130
Benjamin G. Davis
5.1 Introduction and Strategy 130
5.1.1 Synthetic Biology as a Parallel to Synthetic
Organic Chemistry 130
5.1.2 Synthetic Biology as the Driver for Chemical
Medicine 132
5.1.3 Current Strategic Small-Mindedness and
Opportunities Beyond It 133
5.1.4 Current Limitations Provide Further
Opportunities 134
VP. uiebwlis Ohendli noen 06 September 2013 on http://pubs.rsc.org | doi:10.1039/9781849737159-FP007
x Contents
5.2 Synthetic Vaccines 135
5.3 Pegylation Technology and the Pegylation of Proteins 137
5.4 Synthetic Biologics with Payloads 139
5.5 Future Prospects and Conclusions 140
References 142
Chapter 6 Recent Advances in Antibody–Drug Conjugates 145
Edmund I. Graziani and L. Nathan Tumey
6.1 Introduction 145
6.2 Recent Developments in ADC Linker Technology 146
6.2.1 Cleavable Linkers 146
6.2.2 Noncleavable Linkers 153
6.2.3 Impact of Linkers on Biophysical Properties 155
6.3 Recent Developments in Site Specific Conjugation
of ADCs 156
6.3.1 Engineered Cysteines 157
6.3.2 Unnatural Amino Acids as Reactive Handles
for Antibody Conjugation 160
6.3.3 Chemical and Enzymatic Methods for
Site-Specific Protein Conjugation 162
6.4 Recent Developments in ADC Metabolism and PK 164
6.4.1 Payload Release In Targeted Tissues 165
6.4.2 Premature Payload Release In Circulation And
Non-Targeted Tissues 166
6.4.3 Pharmacokinetics/Pharmacodynamics 167
6.4.4 ADC Clearance and Elimination 168
6.5 Summary and Future Prospects 169
References 170
Chapter 7 MicroRNA Biotherapeutics: Key Challenges from a Drug
Development Perspective 176
Sterghios Athanasios Moschos
7.1 Introduction 176
7.2 MicroRNA Biogenesis 180
7.2.1 Genomic Organization of Endogenous
miRNAs 181
7.2.2 Virus-Encoded miRNAs 182
7.2.2.1 Herpesviruses 182
7.2.2.2 Adenovirus 183
7.2.2.3 RNA Viruses: an Unlikely, yet
Flexible Group of Vectors 183
7.2.3 Canonical miRNA Maturation 184
7.2.3.1 Excision of miRNA Precursors from
Primary Transcripts 185
7.2.3.2 Nuclear Export of Pre-miRNAs 186
VP. uiebwlis Ohendli noen 06 September 2013 on http://pubs.rsc.org | doi:10.1039/9781849737159-FP007