Antibodies for Treating. Cancer Basics, Development, and Applications

153 Pages·2015·4.868 MB·English

by  Melvyn Little

Antibodies
for Treating
Cancer
Basics, Development, and
Applications
Melvyn Little
123
Antibodies for Treating Cancer
Melvyn Little
Antibodies for Treating
Cancer
Basics, Development, and Applications
Melvyn Little
Sankt Peter-Ording
Schleswig- Holstein
Germany
Based on the German language edition:
Antikörper in der Krebsbekämpfung by Melvyn Little
Copyright © Springer-Verlag Berlin Heidelberg 2015. All Rights Reserved.
ISBN 978-3-030-72598-3 ISBN 978-3-030-72599-0 (eBook)
https://doi.org/10.1007/978-3-030-72599-0
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2021
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Dedicated to the memory of the late Jim
Huston, creator of the single-chain antibody
and founding President of the Antibody
Society.
Preface
Nothing was known about the existence of antibodies when the first safe and effec-
tive vaccine against smallpox was tested by Edward Jenner on his gardener’s son in
1796. It was only recently, about 200 years later, with a better understanding of the
immune system and the biology of tumor cell development, that the first vaccines
were developed against certain types of cancer.
The advent of recombinant DNA technology in the 1970s and the groundbreak-
ing production of monoclonal antibodies by Köhler and Milstein in 1975 opened
up an exciting era for developing antibodies to treat cancer. Their sequences were
humanized to make them less immunogenic and functional features were opti-
mized for mediating tumor cell killing. Emulating Paul Ehrlich’s concept of “magic
bullets,” they were also armed with toxins and radioactive nuclides. To harness
cytotoxic immune cells, dual-binding (bispecific) antibodies were created by join-
ing domains directed against cytotoxic T lymphocytes or natural killer (NK) cells
with antibody domains binding to specific markers on the tumor cell surface. In
another approach, antibody binding domains were used to construct chimeric anti-
gen receptors (CARs) for engineering cytotoxic T cells to target and destroy can-
cer cells.
Solid tumors are complex tissues often containing many different cell types that
form the tumor stroma. An understanding of their interactions is essential for devis-
ing novel immunotherapeutic approaches. The discovery that the inhibition of the
cytotoxic activity of tumor-infiltrating lymphocytes by the immunosuppressive
tumor microenvironment could be blocked by antibodies against immune check-
points (ICs) led to a breakthrough in the treatment of some solid tumors. A signifi-
cant number of complete remissions have been achieved for previously recalcitrant
cancers such as malignant melanomas and even lung cancers can now be treated
with anti-ICs as part of a first-line therapy.
The goal of this book is to provide medical and biology students, lecturers, phy-
sicians, clinicians, and research workers with a concise description of antibodies
being developed and used for the treatment of cancer. To demonstrate their potential
benefits and possible side effects, I have summarized the results of clinical trials for
a variety of approved antibodies. A short history of immunization and the elucida-
tion of antibody structure and diversity provide a background perspective, and a
vii
viii Preface
short overview of the immune system facilitates a better understanding of antibody
functions and novel immunotherapeutic approaches. I have also included several
anecdotes to “humanize” various aspects of antibody developments.
Sankt Peter-Ording, Germany Melvyn Little
January 2021
Contents
1 Life-Saving Antibodies: History of Immunization . . . . . . . . . . . . . . . . . 1
2 Antibodies and the Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3 Current Approaches for Immunizing Against Cancer . . . . . . . . . . . . . 25
4 Generation, Structure, and Function of Antibodies . . . . . . . . . . . . . . . 35
5 Of Mice and Men: Production of Therapeutic Antibodies . . . . . . . . . . 47
6 Mediation of Tumor Cell Death by Naked Antibodies. . . . . . . . . . . . . . 57
7 Antibodies as Magic Bullets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
8 Novel Modular Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
9 Recruiting Killer Cells for Cancer Therapy . . . . . . . . . . . . . . . . . . . . . . 109
10 Cancer Incidence: Market for Therapeutic Antibodies . . . . . . . . . . . . 127
11 Outlook. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
ix
About the Author
Melvyn Little
– B.Sc. in Chemistry and Ph.D. in Biochemistry,
University College of North Wales, Bangor, UK
– Postdoc Max-Planck-Institute of Cell Biology,
Wilhelmshaven, Germany
– Research scientist at the German Cancer Research
Center (DKFZ) in Heidelberg, Germany
– Habilitation in the Faculty of Biology at the
University of Heidelberg: “Structure and Function of
Microtubules”
– External Professor of Biochemistry at the University
of Heidelberg
– Head of the research group “Recombinant
Antibodies” at the German Cancer Research Center,
Heidelberg
– Founder and Chief Scientific Officer of the biotech
company Affimed—Development of bispecific anti-
bodies for treating cancer
– Currently retired and biotechnology consultant
xi
Life-Saving Antibodies: History 1
of Immunization
Abstract
In 1796, Edward Jenner scraped pus from the blisters of a milkmaid infected
with cowpox, which he inoculated into the arms of his gardener’s son to protect
him from smallpox. Almost a century later, Louis Pasteur developed vaccina-
tions against diseases such as anthrax and rabies using weakened pathogens.
Shortly afterwards, Emil von Behring, Kitasato Shibasaburō, and Paul Ehrlich
demonstrated that antitoxins in the serum of horses vaccinated with diphtheria
toxin could cure diphtheria patients. The complementary lock and key binding of
the antitoxin (antibody) with the toxin (antigen) postulated by Paul Ehrlich was
confirmed 40 years later by Linus Pauling. As a direct result of the work of these
early pioneers, successful vaccination campaigns have been carried out against
various pathogens in the past 50 years. More recently, advances in the isolation
and genetic engineering of antibodies against tumor-associated antigens have
opened up new possibilities for treating cancer.
1.1 Introduction
One of the greatest achievements of modern medicine was the complete eradication
of smallpox through a worldwide vaccination program. Can similar successes in
combating cancer with vaccines be expected? Would it be possible to use the anti-
bodies generated by vaccines for cancer therapy as in the original treatment of diph-
theria? For better understanding the possibilities of vaccination and the recent
innovative approaches in using antibodies to fight cancer, an overview of the histori-
cal development of immunization provides an interesting background perspective.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 1
M. Little, Antibodies for Treating Cancer,
https://doi.org/10.1007/978-3-030-72599-0_1