Antibody Therapeutics

385 Pages·1997·29.055 MB·\385

by  William J. Harris (Editor), John R. Adair (Editor)

ANTIBODY
THERAPEUTICS
Pharmacology and Toxicology: Basic and Clinical Aspects
Mannfred A. Hollinger, Series Editor
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Inflammatory Cells and Mediators in Bronchial Asthma, 1990,
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Antibody Therapeutics, 1997, William J. Harris and John R. Adair
Muscarinic Receptor Subtypes in Smooth Muscle, 1997, Richard M. Eglen

ANTIBODY
THERAPEUTICS
Edited by
William J. Harris, Ph.D.
University of Aberdeen
Aberdeen, Scotland
John R. Adair, Ph.D.
Axis Genetics, Pie.
Babraham, Cambridge, United Kingdom
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INTRODUCTION
John R. Adair
Immunotherapy is now into its second century of application. 1
From the early use of serum therapy in the last years of the 19th Century
to today when large numbers of monoclonal antibodies 2 (MAbs) and
polyclonal antibody cocktails are being tested for efficacy in a variety
of medical conditions the concept of the "magic bullet" has never
disappeared.
Antibodies have much to offer as pharmaceuticals. Immunoglob-
ulin is a safe, long-lasting, naturally occurring product, present in the
blood at 10-15 mg/ml. A vast range of antibody specificities of high
affinity can be generated. The affinity of an antibody for antigen, for
example, a cell-surface receptor, can exceed the affinity of the natural
ligand for that receptor, and so antibodies can be considered for a range
of therapeutic opportunities, from simple blockade (which includes
entry of pathogens into cells) to sophisticated modulation of intracel-
lular signaling, cell stimulation, anergy, or killing.
Today the ability to generate specific human or human-like binding
sites from a number of starting positions is relatively straightforward
(see, for example, References 3 and 4). These binding sites can be linked
genetically or chemically to a wide variety of effector elements, in a
range of size and avidity formats.5 The products can be produced in a
range of expression systems, offering high productivity and accurate
processing. This modular approach to design can overcome many of
the traditionally posed problems for antibody products, for example,
immunogenicity, lack of efficacy, and inappropriate pharmacokinetics.
The development of these engineered products has taken place
over the last 20 years, post Kohler and Milstein. 2 Production of MAbs
from cell culture increased the specific activity of an antibody prepa-
ration, offering a potential reduction in the amount of antibody to be
delivered or delivery of an efficacious dose of antibody in a reasonable
formulation, thus widening the scope for therapeutic applications.
MAbs also removed the problem of transfer of unnecessary blood
components in immune globulin preparations and of adventitious
infectious organisms.
A number of phases can be identified in this period. Between
1975-1980 murine MAbs were prepared against a range of clinically
relevant antigens including tumor-associated antigens, infectious
microorganisms, blood proteins, and cell-surface antigens. For exam-
ple, the murine anti-human CD3 MAb OKT3 was developed in 1979
and subsequently licensed in 1986 as ORTHOCLONE OKT®3 for use
as an immunosuppressant for treatment of transplant rejection.6 In
parallel, attempts were made during this time to derive human MAbs,
but without much success (reviewed in Reference 7).
During the period between 1980-1985 recombinant DNA tech-
niques and expression technologies were applied to the antibody field.
The gene structures of immunoglobulins were revealed and methods
for the manipulation of antibody sequences and their expression in
heterologous systems were first developed. The first domain swapping
experiments to produce chimeric mouse-human antibodies were
described,89 the possibility of antibody humanization was proposed,10
and early experiments to generate transgenic mice expressing human
antibody genes were done.11 The concept of catalytic MAbs was dis-
cussed.12 Several important intellectual property claims were made
during this period (summarized in Reference 13), some of which are
still being argued over.
Between 1986-1990 commercial antibody engineering began to be
taken seriously and many important developments occurred. The
range of possible antibody-based products widened with the genera-
tion of recombinant antibody fragments,1416 antibody binding sites
fused to other protein entities (reviewed in References 17-20), and non-
antibody binding sites linked to antibody Fc regions (immunoadhesins
and receptor globulins).2122 Bacterial expression systems became avail-
able for the efficient production of these novel entities,1415 while mam-
malian cell23 and yeast24 systems were developed for whole antibody
production based on other examples from the biotechnology industry.
These systems allowed production levels in excess of that produced by
hybridomas in cell culture. During this period the first humanized
antibodies were produced,25 and the first recombinant antibodies
entered clinical studies.26-27
In the period from 1990 to the present, these achievements have
been further developed with a wide range of engineered antibodies
entering clinical studies. The rate of entry into clinical trials of these
product candidates is accelerating; for example, the number of human-
ized antibodies in the clinic has doubled in the last 12 months. 2829 One
of these engineered antibodies has already emerged as a product. Fur-
ther developments include: the addition of combinatorial library pro-
cedures for the production of novel human antibodies;34 progress in in
vitro immunization as a means of generating novel specificities (e.g.,
Reference 30); a clearer understanding of the measures needed to be
taken to ensure efficient humanization of the vast range of nonhuman
MAbs which now exist;31 and the use of antibodies as platforms for the
presentation of antigenic peptides (reviewed in Reference 32). Explicit
links to the pharmaceutical drug development process have been made
using antibody33 or minibody34 library screening systems, and the use
of anti-receptor antibodies to prepare secondary structure mimics of
interesting ligands.35 In addition, large-scale production systems have
now progressed to the point where economical production is
feasible36-38 (see also Chapters 9 and 10) which should allow the use of
human and humanized antibodies as chronic, as well as acute treat-
ments. Novel expression systems have also emerged that may ulti-
mately challenge the more traditional methods for cost-effective
production3940 (see Chapter 11).
This book developed from a wish to present a timely summary of
the progress of antibody products through development and clinical
studies into the market place. Therefore, a focus of the book is with
these latter phases of engineered antibody development.
This book is divided into a number of sections. In the first section
the chapters describe recent developments in antibody R+D which will
provide the platform for further product development. The focus is on
how the antibody achieves a therapeutic effect post-binding. M. Clark
(Cambridge) has reviewed recent progress in the use of unconjugated
antibodies as therapeutics, including their use in antigen blockade,
recruitment of antibody-dependent cellular cytotoxicity (ADCC) and
complement, and situations where bispecific antibodies might be of
benefit. Three chapters then describe the use of antibodies for delivery
of toxins (R. Kreitman and I. Pastan, NIH), drugs and radioisotopes
(G. Yarranton, Celltech), and enzymes for the activation of prodrugs
(I. Benhar and I. Pastan, NIH). These chapters principally deal with the
use of antibodies for treatment of cancers, which has been a major focus
of antibody therapeutics development. Chapters in the next section
identify alternative uses for antibody therapeutics.
The second section provides an insight into areas where antibodies
are being considered as products. Recent surveys of antibodies in
development2941 suggest that while there is still a predominance in the
use of antibodies as anti-cancer platforms, recombinant MAbs are being
considered for use in a much broader range of indications. The use of
antibodies for the treatment of cancer is not dealt with here as a separate
subject as it has been reviewed extensively elsewhere and permeates
many of the other individual chapters in Sections I and IV. W. Harris
(Aberdeen) summarizes the use of immune globulins and MAbs in the
treatment of infectious diseases. L. Chatenoud (Oxford) describes
opportunities for the use of antibodies in autoimmune situations.
ORTHOCLONE OKT®3 has been licensed for use in renal transplanta-
tion for 10 years. M. Alegre (Belgium) provides an update on the