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Novel Therapeutic Proteins
Selected Case Studies

Edited by Klaus Dembowsky

and Peter Stadler

@WILEY-VCH
Novel Therapeutic
Proteins
Selected Case Studies

Edited by Klaus Dembowsky

and Peter Stadler

@WILEY-VCH
Weinheim . New York . Chichester
Brisbane . Singapore . Toronto
Editors:
Dr. Klaus Denlbowsky Prof. Dr. Peter Stadlcr
Bayer AG Artemis Pharmaceuticals
c/o Millennium Pharmaceuticals, Inc. Geschaftsfuhrung
75 Sidnev Street Neurather Ring 1
Cambridge, MA 02139 D-51063 Koln
USA Germany

This book was carefully produced. Nevertheless, editors, authors, and publisher do not war-
rant the information contained therein to be free of errors. Readers are advised to keep in
mind that statements, data, illustrations, procedural details or other items may inadvertently
be inaccurate.

Library of Congress Card No.: applied for

British Library Cataloguing-in-Publication Data:

A cataloue record for this book
is available from the British Library

Die Deutsche Bibliothek - CIP-Einheitsaufnahme

A catalogue record for this book is available from Die Deutsche Bibliothek
ISBN 3-527-30270-0

0 WILEY-VCH Verlag GmbH, D-69469 Weinheim (Federal Republic of Germany), 2001

Printed on acid-free paper

All rights reserved (including those of translation into other languages). No part of this book may be
reproduced in any form - by photoprinting, microfilm, or any other means - nor transmitted or
translated into a machine language without written permission from the publishers. Registered
names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be
considered unprotected by law.

Composition: Hagedorn Kommunikation, Viernheim

Printing: betz-druck, Darmstadt
Bookbinding: W. Osswald, NeustadtlWstr.
Foreword

In 1944, Oswald Avery and his colleagues McLeod and MacCarty at Rockefeller
University made one of the most consequential discoveries of the 20th century:
they showed deoxyribonucleic acid (DNA) to be the carrier of genetic information.
While their results were largely ignored by the public at large they sent ripples
through the scientific community. Nine years later, James Watson and Francis
Crick elucidated the structure of this molecule, which was compelling in its sheer
beauty in the first place. In addition, however, through the feature of base comple-
mentarity, it pointed towards possible mechanisms of DNA replication, transcription
and even translation.
Within the short time span of only twenty five years, a new science evolved. Mo-
lecular biology opened a new era in biology and medicine and spawned a new indus-
try, the biotechnology industry. The initial achievements of this industry can be sum-
marized by two technical terms : recombinant proteins and monoclonal antibodies.
Driven by a rapid rate of progress in molecular biology, cell biology, fermentation
and in related disciplines, the industry learned to clone and to express genes specify-
ing the synthesis of medically important peptides and proteins. It also learned to pro-
duce and to develop these novel products, many of which have greatly enriched the
therapeutic repertoire of medicine. The biotech industry has since broadened its scale
of activity immensely. It is, in fact, in the process of becoming the discovery arm of
the pharmaceutical industry.
The present book, however, summarizes some of the fundamental early achieve-
ments of biotechnology. Recombinant peptide hormones, cytolunes, enzymes, recep-
tors, vaccines and monoclonal antibodies are presented by authors who have made
important contributions to the discovery, the characterization and the medical use
of these proteins. In this age of rapid changes and surprising new developments, it
has become impossible to represent any subject matter of high complexity in com-
plete detail. Nevertheless, the book succeeds in giving a broad and solid account
of the first wave of biotechnological achievements. Anyone who browses through
this volume and reads single chapters or sections in greater detail cannot help to
be impressed by the enormous ground that was covered by biological science and
technology during only a few decades. In this sense, the book may achieve two
goals : for those who have consciously witnessed the heroic period of biotechnology
this volume will provide a valuable system of reference and a reliable source of in-
formation. For those who still underestimate the role of biotechnology in medicine
this book provides living testimony to the fact that biotechnology is not a passing
fancy, but represents irrefutable reality. Beyond doubt, many new recombinant pro-
teins and monoclonal antibodies are yet to be discovered and developed. The eluci-
dation of the human genome nucleotide sequence is creating a wealth of exciting new
information which will be utilized as it emerges. This is to say that even the first
wave of biotechnology has not yet reached its peak. Much more is to come.
VI Foreword

The authors and editors are to be congratulated for creating a book that is equally
appealing to scientists in academia and industry, to physicians and even to graduate
students in the biological sciences, in biochemistry and in medicine.

Feldafing, October 2000 Jiirgen Drews

Preface

For many decades now, proteins have been well accepted as a therapeutic principle in
medicine, insulin being but one example. Isolated from organs and plasma of humans
and other species, their use was initially limited by the number and supply of prod-
ucts available for therapy. Then, in the late 1980s, serious safety concerns, e. g., con-
taminations of products by viruses originating from the used raw material, were
raised which further restricted their use in medicine.
Concomitantly, biotechnology and molecular biology had ripened and enabled the
large-scale production of existing therapeutic proteins and the introduction of novel
proteins according to strict safety guidelines. To begin with, hybridoma technology
was used, but the major breakthrough came with genetic engineering and recombi-
nant methodology. In 1978 the first human recombinant protein, insulin, was pro-
duced by expression in E. coli and finally approved for medical use in 1982.
Today the success of biotechnology in medicine is undisputable: it is best illustrated
by the 350 and more biotechnological products that are currently being tested in clin-
ical trials or are already on the market. These products are mostly recombinant pro-
teins, including monoclonal antibodies, that fall into the two categories of therapeutic
and diagnostic agents. In therapy they allow treatment regimens for diseases that thus
far could not be treated adequately with conventional chemical drugs. Examples are
erythropoietin for anemia associated with chronic renal failure and etanercept for
rheumatoid arthritis. Some of the products, e. g., insulin, erythropietin, G-CSF, or
coagulation factor VIII are very successful and reach sales figures of the same mag-
nitude as blockbuster chemical drugs.
After the human genome was deciphered in the year 2000, the functions of the
newly discovered genes need to be elucidated. Once this is accomplished, many
more novel products are anticipated for the therapy of diseases that have eluded ef-
fective treatment until now.
This book is the first comprehensive compilation of medical applications of re-
combinant proteins and monoclonal antibodies, some of which have already been
on the market for several years, while others have only recently been launched. It
also highlights the manufacturing processes for individual products, the strategies
that were taken by companies in the clinical development as well as the hurdles
that were encountered in clinical trials and had to be overcome before approval by
regulatory authorities. Finally, the book illustrates strategies to modify and improve
the pharmacodynamic and pharmacokinetic properties of naturally occurring proteins
thus paving the way for a new era in biotechnology, i. e., protein engineering.
We would like to express our gratitude and appreciation to the authors for their
effort and cooperation. Their expertise provides an outstanding contribution to
the success of the respective recombinant protein or monoclonal antibody. We also
gratefully acknowledge the continuous and encouraging support of Karin Dembow-
sky and her staff at WILEY-VCH in the realization of this book.

Cambridge, MA, and Koln, Klaus Dembowsky,

October 2000 Peter Stadler
Contents

Foreword . . . . . . . . . . . . . . . . V
Jiirgen Drews

Preface . . . . . . . . . . . . . . . . . . . . VII
Klaus Deinbowsky and Peter Stadler

Introduction and Overview

1 Medical Applications of Recombinant Proteins in Humans . . 3
Gayle Delmonte Wetzel
1.1 Introduction . . . . . . . . . . . . . . . . . . . . 3
1.2 Presently Approved Biotech Products . . . . . . . . . . 4
1.3 Biotechnology Products in Clinical Development . . . . . . 7
1.4 Specific Diseases and Applications . . . . . . . . . . . 13
1.4.1 Myocardial Infarction and Stroke . . . . . . . . . . . . 13
1.4.2 Heart Failure . . . . . . . . . . . . . . . . . . 14
1.4.3 Fibrosis . . . . . . . . . . . . . . . . . . . . 14
1.4.4 Osteoporosis . . . . . . . . . . . . . . . . . . . 15
1.4.5 Obesity. Insulin Resistance.
and Non-Insulin Dependent (Type 11) Diabetes . . . . . . . 15
1.4.6 Sepsis . . . . . . . . . . . . . . . . . . . . . 15
1.4.7 Immunoenhancement . . . . . . . . . . . . . . . . 16
1.4.7.1 Tumor Therapy . . . . . . . . . . . . . . . . . . 16
1.4.7.2 Vaccines . . . . . . . . . . . . . . . . . . . . 16
1.4.8 Immune Deviation . . . . . . . . . . . . . . . . . 18
1.4.9 Multiple Sclerosis (MS) . . . . . . . . . . . . . . . 18
1.4.10 Psoriasis . . . . . . . . . . . . . . . . . . . . 18
1.4.11 Arthritis . . . . . . . . . . . . . . . . . . . . 19
1.4.12 Inflammatory Bowel Disease . . . . . . . . . . . . . 19
1.4.13 Allergy and Asthma . . . . . . . . . . . . . . . . 19
1.4.14 Replacement Therapies . . . . . . . . . . . . . . . 20
1.4.15 Viral Infections . . . . . . . . . . . . . . . . . . 20
1.4.16 Reproductive Medicine . . . . . . . . . . . . . . . 21
1.4.17 Other . . . . . . . . . . . . . . . . . . . . . 21
1.5 Conclusion . . . . . . . . . . . . . . . . . . . 21
1.6 References . . . . . . . . . . . . . . . . . . . 23
X Contents

Recombinant Hormones
2 Clinical Applications of Recombinant Human Erythropoietin . 29
Dimitrios Spentzos and Arthur J . Sytkowski
2.1 Structure of Human Erythropoietin . . . . . . . . . . . 29
2.2 General Principles . . . . . . . . . . . . . . . . . 31
2.3 Medical Applications of Recombinant Human EPO . . . . . 33
2.3.1 The Anemia of Chronic Renal Failure (CRF) . . . . . . . 33
2.3.2 Acquired Immunodeficiency Syndrome (AIDS) . . . . . . . 34
2.3.3 Chemotherapy Induced Anemia of Non-Hematologic Malignancies 36
2.3.4 The Perioperative Setting . . . . . . . . . . . . . . 37
2.3.4.1 Recombinant Human EPO without Autologous Blood Donation . 37
2.3.4.2 Recombinant Human EPO as an Adjunct to
Autologous Bood Donation . . . . . . . . . . . . . 38
2.3.5 The Anemia of Prematurity . . . . . . . . . . . . . 39
2.3.6 The Anemia of Hematologic Malignancies . . . . . . . . 40
2.3.7 Myelodysplastic Syndromes and Other Hematologic
Stem Cell Disorders . . . . . . . . . . . . . . . . 41
2.3.8 Bone Marrow Transplantation (BMT) . . . . . . . . . . 42
2.3.9 The Hemoglobinopathies . . . . . . . . . . . . . . 43
2.3.10 The Anemia of Chronic Inflammation . . . . . . . . . . 43
2.4 Patient Response and Medical Economics . . . . . . . . . 44
2.5 Pharmacokinetics : Dosage. Routes of Administration.
and Effect Monitoring . . . . . . . . . . . . . . . 45
2.6 Iron Supplementation during rhEPO Treatment . . . . . . . 46
2.7 Future Directions . . . . . . . . . . . . . . . . . 47
2.8 References . . . . . . . . . . . . . . . . . . . 48

3 Human Recombinant Growth Hormone . . . . . . . . . 59

Carmen Ariznavarreta Ruiz and J e s h A.F: Tresguerres
3.1 Introduction . . . . . . . . . . . . . . . . . . . 59
3.2 Hypothalamic Regulation . . . . . . . . . . . . . . 62
3.2.1 Somatostatin . . . . . . . . . . . . . . . . . . . 62
3.2.2 Growth Hormone Releasing Hormone . . . . . . . . . . 62
3.2.3 Other Neurotransmitters . . . . . . . . . . . . . . . 64
3.3 Peripheral Regulation of GH . . . . . . . . . . . . . 64
3.4 Mechanisms of Action of GH . . . . . . . . . . . . . 66
3.4.1 GH Receptor . . . . . . . . . . . . . . . . . . 66
3.4.2 Metabolic Effects . . . . . . . . . . . . . . . . . 66
3.4.3 Insulin Growth Factors (IGF) . . . . . . . . . . . . . 67
3.4.3.1 Circulation of IGF . . . . . . . . . . . . . . . . . 68
3.4.3.2 Receptors of IGF . . . . . . . . . . . . . . . . . 68
3.4.3.3 Actions of IGF . . . . . . . . . . . . . . . . . . 69
 Contents XI

3.5 GH Effects on Growth . . . . . . . . . . . . . . . 69

3.5.1 Dwarfism . . . . . . . . . . . . . . . . . . . . 69
3.5.2 Gigantism . . . . . . . . . . . . . . . . . . . 70
3.5.3 Acromegaly . . . . . . . . . . . . . . . . . . . 70
3.5.4 GH Deficiency in the Adult . . . . . . . . . . . . . 71
3.6 Production of GH . . . . . . . . . . . . . . . . . 71
3.6.1 Preparations Obtained by Extractions . . . . . . . . . . 71
3.6.2 Genetic Engineering of GH . . . . . . . . . . . . . 72
3.6.2.1 Synthesis in Prokaryotic Cells . . . . . . . . . . . . . 72
3.6.2.2 Second Synthetic Procedure for GH Synthesis . . . . . . . 73
3.6.2.3 Third Synthetic Procedure for GH Synthesis . . . . . . . . 74
3.6.2.4 Synthesis of hGH in Eukaryotic Cells . . . . . . . . . . 74
3.7 Therapy with GH . . . . . . . . . . . . . . . . . 78
3.7.1 Use of rhGH in the Treatment of GH Defiency . . . . . . . 78
3.7.2 Use of rhGH in Chronic Renal Failure (CRF) . . . . . . . 79
3.7.3 Use of rhGH in Turner's Syndrome . . . . . . . . . . . . 80
3.7.4 Use of GH in Different Catabolic States and in AIDS . . . . 80
3.8 References . . . . . . . . . . . . . . . . . . . 82

4 Human Recombinant Follicle Stimulating Hormone

(Follitropin-a) . . . . . . . . . . . . . . . . . . 87
Jose' A . Peinado. Colin M . Howles. Jesu's A . F: Tresguerres
4.1 Introduction . . . . . . . . . . . . . . . . . . . 87
4.2 The Structure of Gonadotropins . . . . . . . . . . . . 88
4.3 Physiology of Gonadotropins . . . . . . . . . . . . . 90
4.4 Hypothalamic Regulation . . . . . . . . . . . . . . 92
4.5 Urinary Gonadotropic Preparations with FSH Activity . . . . 93
4.6 Gonadotropin Production Using Recombinant DNA Technology . 94
4.7 Physicochemical and Pharmacological Characteristics of rhFSH . 97
4.7.1 Physical Properties . . . . . . . . . . . . . . . . 97
4.7.2 Recombinant FSH Isoforms . . . . . . . . . . . . . 98
4.7.3 Pharmacokinetic Characteristics . . . . . . . . . . . . 99
4.7.4 Clinical Pharmacology . . . . . . . . . . . . . . . 99
4.8 Clinical Applications of rhFSH . . . . . . . . . . . . 100
4.8.1 WHO Group I Anovulation (Hypogonadotropic Hypogonadism) . 100
4.8.2 WHO Group I1 Anovulation . . . . . . . . . . . . . 100
4.8.3 Ovarian Stimulation Prior to IUI . . . . . . . . . . . . 103
4.8.4 Role of rhFSH in Assisted Reproduction . . . . . . . . . 103
4.8.5 Recombinant Gonadotropins . the Future . . . . . . . . . 106
4.9 References . . . . . . . . . . . . . . . . . . . 107
XI1 Conterits

Recombinant Cytokines and their Receptors

5 Granulocyte Colony Stimulating Factor (G-CSF) . . . . . . 115
Karl Welte
5.1 Introduction . . . . . . . . . . . . . . . . . . .
5.2
5.3
5.3.1
5.3.2 Bone Marrow Transplantation (BMT) and Peripheral Blood
Progenitor Cell (PBPC) Transplantation . . . . . . . . . 119
5.3.3 Severe Chronic Neutropenia . . . . . . . . . . . . . 120
5.4 Potential Future Indications . . . . . . . . . . . . . 122
5.4. I Neutropenia Associated with HIV Infection and AIDS . . . . 122
5.4.2 Aplastic Anemia . . . . . . . . . . . . . . . . . 122
5.4.3 Severe Autoimmune Diseases . . . . . . . . . . . . . 123
5.4.4 Granulocyte Transfusions . . . . . . . . . . . . . . 123
5.5 Safety . . . . . . . . . . . . . . . . . . . . . 123
5.6 Summary and Conclusions . . . . . . . . . . . . . . 124
5.7 References . . . . . . . . . . . . . . . . . . . 124

6 Interferon B-lb in Multiple Sclerosis . . . . . . . . . . 129

Bernd Aufdembrinke. Reinhard Horowski.
and Joachim-Friedrich Kapp
6.1 Introduction . . . . . . . . . . . . . . . . . . . 129
6.2 Natural Interferons and Early Treatment Rationale
in Multiple Sclerosis . . . . . . . . . . . . . . . . 131
6.3 Recombinant Interferons and New Treatment Rationales
in Multiple Sclerosis . . . . . . . . . . . . . . . . 132
6.4 Production of Recombinant Human IFNP-lb . . . . . . . 133
6.5 IFNP-lb in Multiple Sclerosis . . . . . . . . . . . . . 134
6.5.1 Pivotal Study of IFNP-lb in Relapsing-Remitting MS . . . . 134
6.5.2 Pivotal Study of IFNP-lb in Secondary Progressive MS . . . . 138
6.6 Questions to be Addressed by Future Clinical Research . . . . 142
6.7 Summary . . . . . . . . . . . . . . . . . . . . 142
6.8 References . . . . . . . . . . . . . . . . . . . 143

7 TNF-a Receptors as Recombinant Proteins in Treatment

of Rheumatoid Arthritis . . . . . . . . . . . . . . 147
Hanns-Martin Lorenz and Joachim R. Kalden
7.1 Introduction . . . . . . . . . . . . . . . . . . . 147
7.2 Soluble TNF-a Receptor p55-IgG1 Construct Lenercept . . . . 149
7.3 Soluble TNF-a Receptor p75-IgG1 Construct
(Etanercept, EnbrelTM) . . . . . . . . . . . . . . . 150
7.4 PEGylated Soluble TNF-a Receptor-p55 . . . . . . . . . 151
7.5 References . . . . . . . . . . . . . . . . . . . 152
 Contents XI11

Recombinant Enzymes. Enzyme Activators. and Inhibitors

8 Improvement of Principles of Nature: t-PA . . . . . . . . 1.57
Rolf G. Werner and Gerhard Heusel
8.1 Introduction . . . . . . . . . . . . . . . . . . . 157
8.2 The Fibrinalytic System . . . . . . . . . . . . . . . 157
8.3 Two Principles of Nature: Urokinase and Tissue Plasminogen
Activator . . . . . . . . . . . . . . . . . . . 158
8.3.1 Urokinase . . . . . . . . . . . . . . . . . . . 158
8.3.2 Tissue Plasminogen Activator . . . . . . . . . . . . . 160
8.4 Structure and Functional Domains of t-PA . . . . . . . . 161
8.4.1 Fibrin Binding Domains . . . . . . . . . . . . . . . 162
8.4.2 Catalytic Domain . . . . . . . . . . . . . . . . . 162
8.4.3 Domains Involved in Clearance of t-PA in vitro . . . . . . . 164
8.4.4 Domains Involved in Binding to Endothelial Cell Receptors . . 16.5
8.5 Successful Development . . . . . . . . . . . . . . . 16.5
8.6 Manufacturing of t-PA . . . . . . . . . . . . . . . 166
8.6.1 Expression System . . . . . . . . . . . . . . . . 166
8.6.2 Production Cell Line . . . . . . . . . . . . . . . . 167
8.6.3 Fermentation Process . . . . . . . . . . . . . . . . 169
8.6.4 Downstream Processing . . . . . . . . . . . . . . . 170
8.6.5 Formulation . . . . . . . . . . . . . . . . . . . 171
8.6.6 Stability . . . . . . . . . . . . . . . . . . . . 171
8.6.7 Evidence of Chemical Structure . . . . . . . . . . . . 173
8.6.8 Potential Impurities . . . . . . . . . . . . . . . . 176
8.7 Toxicological Evaluation of t-PA . . . . . . . . . . . . 178
8.8 Clinical Experience with t-PA . . . . . . . . . . . . . 180
8.8.1 Acute Myocardial Infarction . . . . . . . . . . . . . 180
8.8.2 Deep Vein Thrombosis . . . . . . . . . . . . . . . 183
8.8.3 Major Pulmonary Embolism . . . . . . . . . . . . . 183
8.8.4 Arterial Thromboembolism . . . . . . . . . . . . . . 184
8.8.5 Acute Ischemic Stroke . . . . . . . . . . . . . . . 184
8.9 Second Generation t-PA Molecules . . . . . . . . . . . 185
8.9.1 Natural t-PA Derivatives: TSV-PA . . . . . . . . . . . 185
8.9.2 Natural t-PA Derivatives: DSPA a1 . . . . . . . . . . . 187
8.9.3 Genetically Modified t-PA Molecules . . . . . . . . . . 189
8.9.3.1 Reteplase . . . . . . . . . . . . . . . . . . . . 189
8.9.3.2 Lanoteplase . . . . . . . . . . . . . . . . . . . 190
8.9.3.3 TNK.tPA . . . . . . . . . . . . . . . . . . . . 192
8.10 Conclusion . . . . . . . . . . . . . . . . . . . 195
8.11 References . . . . . . . . . . . . . . . . . . . 196
XIV Contents

9 The Clinical Development of Recombinant Coagulation

Factor VIII (Kogenate@)for the Treatment of Hemophilia A . 203
Peter J . Larson
9.1 Introduction . . . . . . . . . . . . . . . . . . . 203
9.2 Process Definition. Formulation. and Preclinical Development
of Kogenate@ . . . . . . . . . . . . . . . . . . 205
9.3 Clinical Development of Recombinant Factor VIII (Kogenate@) . 206
9.3.1 Kogenate@:Stage 1 - Pharmacokinetic Behavior
and Initial Safety Experience . . . . . . . . . . . . . 208
9.3.2 Kogenate@:Stage 2 .Safety and Efficacy in Home Treatment . . 209
9.3.3 Kogenate@:Stage 3 . Efficacy in Surgery and Serious Bleeding . 210
9.3.4 Kogenate@:Stage 4 . Safety and Efficacy in Previously
Untreated Patients . . . . . . . . . . . . . . . . . 210
9.3.5 Kogenate@:Safety and Efficacy in Previously Treated
Patients . Japan . . . . . . . . . . . . . . . . . 211
9.4 Safety and Efficacy of [email protected] Experience . 211
9.4.1 German Post Marketing Surveillance Study . . . . . . . . 211
9.4.2 Canadian Inhibitor Surveillance Study . . . . . . . . . . 212
9.4.3 Continuous Infusion . . . . . . . . . . . . . . . . 213
9.4.4 Immune Tolerance Induction . . . . . . . . . . . . . 214
9.5 The Life Cycle of Recombinant Factor VIII (Kogenate@) . . . 215
9.6 Sucrose Formulated Recombinant Factor VIII (Kogenate@FS
or KOGENATE@Bayer) . . . . . . . . . . . . . . . 215
9.6.1 Process Development of Sucrose Formulated Recombinant
Factor VIII (Kogenate@FS or KOGENATE@Bayer) . . . . . . 215
9.6.2 Preclinical Studies of Sucrose Formulated Recombinant Factor VIII
(Kogenate@FS or KOGENATE@Bayer) . . . . . . . . . 216
9.6.3 Guidance on Conduct of Clinical Trials for Hemophilia Products . 216
9.6.4 Clinical Development of Kogenate@FS/KOGENATE@Bayer . . 218
9.7 Conclusion . . . . . . . . . . . . . . . . . . . 221
9.8 References . . . . . . . . . . . . . . . . . . . 222

10 Aprotinin. Recombinant Aprotinin. and Recombinant

Aprotinin Mutants . . . . . . . . . . . . . . . . 225
Klaus Dembowsky and Werner Schroeder
10.1 Introduction . . . . . . . . . . . . . . . . . . . 225
10.2 Inhibitory Profile of Aprotinin . . . . . . . . . . . . . 228
10.3 Reduction of Surgical Blood Loss by Aprotinin . . . . . . . 229
10.3.1 Coronary Artery Bypass Graft Surgery with Open Heart Surgery
and Cardiopulmonary Bypass . . . . . . . . . . . . . 229
10.3.1.1 Mechanism(s) of Action . . . . . . . . . . . . . . . 229
10.3.1.2 Clinical Studies . . . . . . . . . . . . . . . . . 231
10.3.2 Other Indications . . . . . . . . . . . . . . . . . 232
10.3.2.1 Liver Transplantation . . . . . . . . . . . . . . . . 233
10.3.2.2 Hip Surgery . . . . . . . . . . . . . . . . . . . 233
 Contents XV

10.4 Recombinant Aprotinin . . . . . . . . . . . . . . . 233

10.5 Human Ortholog Proteins of Bovine Aprotinin . . . . . . . 234
10.6 Aprotinin Mutants . . . . . . . . . . . . . . . . . 235
10.7 Summary . . . . . . . . . . . . . . . . . . . . 237
10.8 References . . . . . . . . . . . . . . . . . . . 238

Recombinant Vaccines
11 Recombinant Hepatitis B Vaccines .Characterization of the
Viral Disease and Vaccine Production in the Methylotrophic
Yeast. Hansenula polymorpha . . . . . . . . . . . 245
Stephan Schaefec Michael Piontek. Sang-Jeom Ahn.
Adam Papendieck. Zbigniew A . Janowicz. and Gerd Gellissen
11.1 Introduction . . . . . . . . . . . . . . . . . . . 245
11.2 Virus and Disease Characteristics . . . . . . . . . . . . 246
11.2.1 The Hepadnaviruses . . . . . . . . . . . . . . . . 246
11.2.2 Subtypes of HBV . . . . . . . . . . . . . . . . . 251
11.2.3 Pathogenesis and Disease . . . . . . . . . . . . . . 252
11.3 Recombinant Vaccine Production . . . . . . . . . . . . 253
11.3.1 Yeasts as Production Organisms . . . . . . . . . . . . 255
11.3.2 The Hansenula polymorpha Expression System . . . . . . . 255
11.3.3 Construction of a H . polymorpha Strain Expressing
the Hepatitis B S Antigen . . . . . . . . . . . . . . 257
11.3.3.1 Expression Cassette and Vector Construction . . . . . . . 257
11.3.3.2 Transformation of H . pozymorpha . . . . . . . . . . . 258
11.3.3.3 Strain Characterization . . . . . . . . . . . . . . . 259
11.3.4 H . polymorpha-Derived HBsAg Production Process . . . . . 260
11.3.4.1 Fermentation (Upstream Process) . . . . . . . . . . . . 260
11.3.4.2 Purification (Downstream Processing) . . . . . . . . . . 262
11.4 The Future of Hepatitis B Vaccination . . . . . . . . . . 264
11.4.1 Current Obstacles . . . . . . . . . . . . . . . . . 264
11.4.2 Alternative Vaccine Strategies . . . . . . . . . . . . . 265
11.4.3 Therapeutic Vaccination . . . . . . . . . . . . . . . 266
11.4.4 Combination Vaccines . . . . . . . . . . . . . . . 266
11.5 Conclusion . . . . . . . . . . . . . . . . . . . 267
11.6 References . . . . . . . . . . . . . . . . . . . 268
XVI Contents

Monoclonal Antibodies
12 Therapeutic Applications of Monoclonal Antibodies:
A Clinical Overview . . . . . . . . . . . . . . . . 277
Mark Sopwith
12.1 Introduction . . . . . . . . . . . . . . . . . . . 277
12.2 Targets for Intervention . . . . . . . . . . . . . . . 280
12.3 Clinical Indications . . . . . . . . . . . . . . . . 282
12.3.1 Cardiovascular and Pulmonary Systems . . . . . . . . . 282
12.3.2 Sepsis Syndrome and Infection . . . . . . . . . . . . 283
12.3.3 Immunosuppression and Transplantation . . . . . . . . . 284
12.3.4 Rheumatoid Arthritis and Autoimmune Disorders . . . . . . 285
12.3.5 Cancer . . . . . . . . . . . . . . . . . . . . 288
12.4 Conclusions . . . . . . . . . . . . . . . . . . . 290
12.5 References . . . . . . . . . . . . . . . . . . . 291

13 Antibody Therapy for Sepsis: Some Lessons Learned . . . . 297

Steven M . Opal
13.1 Introduction . . . . . . . . . . . . . . . . . . . 297
13.2 Rationale for Monoclonal Antibody Therapy in Sepsis . . . . 298
13.2.1 Anti-Endotoxin Monoclonal Antibodies . . . . . . . . . 298
13.2.2 Anti-TNF Monoclonal Antibodies . . . . . . . . . . . 301
13.3 Lessons Learned from Preclinical Studies and
Clinical Trial Design . . . . . . . . . . . . . . . . 304
13.3.1 Lessons Learned from Animal Models of Sepsis . . . . . . 304
13.3.2 Problems with Definitions of Sepsis . . . . . . . . . . . 305
13.3.3 Lessons Learned about Clinical Trial Design . . . . . . . . 306
13.4 Summary and Recommendations . . . . . . . . . . . . 308
13.5 References . . . . . . . . . . . . . . . . . . . 309

14 An Engineered Human Antibody for Chronic Therapy:

CDP571 . . . . . . . . . . . . . . . . . 311
Mark Sopwith and Sue Stephens
14.1 Introduction . . . . . . . . . . . . . . . . . . . 311
14.2 Generation of Engineered Human Antibody. CDP571 . . . . . 313
14.3 Preclinical Studies with CDP571 in Non-Human Primates . . . 313
14.4 Studies with CDP571 in Humans . . . . . . . . . . . 314
14.4.1 Safety. Pharmacokinetics. and Antibody Responses in
Human Volunteers . . . . . . . . . . . . . . . . . 314
14.4.2 Single-Dose Studies in Patients . . . . . . . . . . . . 314
14.4.3 Repeated-Dose Study in Patients with Rheumatoid Arthritis
and Crohn’s Disease . . . . . . . . . . . . . . . . 315
14.4.4 Pharmacokinetics and Antibody Responses . . . . . . . . 319
14.5 Conclusions . . . . . . . . . . . . . . . . . . . 321
14.6 References . . . . . . . . . . . . . . . . . . . 321
 Contents XVII

15 The Evolution of ReoPro' Clinical Development . . . . . . 323

Catherine F: Farrell. Elliot S . Barnathan. and Harlan I;: Weisrnan
15.1 Introduction . . . . . . . . . . . . . . . . . . . 323
15.2 Clinical Trials . . . . . . . . . . . . . . . . . . 326
15.2.1 EPIC . . . . . . . . . . . . . . . . . . . . . 326
15.2.2 EPILOG . . . . . . . . . . . . . . . . . . . . 329
15.2.3 CAPTURE . . . . . . . . . . . . . . . . . . . 330
15.2.4 EPISTENT . . . . . . . . . . . . . . . . . . . 332
15.2.5 Combined Results of PCI Trials . . . . . . . . . . . . 334
15.2.6 Trials with Combined ReoPro' and Fibrinolytic Agents . . . . 335
15.2.6.1 SPEED . . . . . . . . . . . . . . . . . . . . 335
15.2.6.2 TIMI-14 . . . . . . . . . . . . . . . . . . . . 336
15.2.6.3 GUSTO IV AM1 . . . . . . . . . . . . . . . . . 337
15.2.7 TIMI-I9 . . . . . . . . . . . . . . . . . . . . 337
15.2.8 Readministration Registry . . . . . . . . . . . . . . 338
15.2.9 GUSTO IVACS . . . . . . . . . . . . . . . . . 339
15.2.10 Stroke . . . . . . . . . . . . . . . . . . . . . 340
15.3 Future Directions in ReoPro@Development . . . . . . . . 341
15.3.1 Facilitated PCI . . . . . . . . . . . . . . . . . . 341
15.3.2 Peripheral Vascular Disease . . . . . . . . . . . . . 342
15.3.3 Sickle Cell Anemia and Cancer . . . . . . . . . . . . 343
15.4 References . . . . . . . . . . . . . . . . . . . 344

Index . . . . . . . . . . . . . . . . . . . . . 347
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