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NOVEL
THERAPEUTIC
AGEN S
for the
TREATMENT
of
AUTOIMMUNE
DISEAS S
edited by
IBEKE RAND
Stanford University School of Medicine
Stanford, California
DAVID L. SCOTT
King's College School of Medicine and DeJr;tfs;trv
and King's College Hospital
London, England
LEES. SIMON
Harvard Medical School
Deaconess Hospital
and Dana-Farber Cancer Institute
Boston, Massachusetts
0 ~'~~,~~~~~"'
Boca Raton London New York
CRC Press is an imprint of the
Taylor & Francis Group, an informa business
First Published by Lawrence Erlbaum Associates, Inc., Publishers
10 Industrial Avenue
Mahwah, New Jersey 07430
Reprinted 2010 by CRC Press
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Library of Congress Cataloging-in-Publication Data
Novel therapeutic agents for the treatment of autoimmune diseases I
edited by Vibeke Strand, David L. Scott, Lee S. Simon.
p. cm.
Includes index.
lSBN 0-8247-9748-5 (hardcover: alk. paper)
l. Autoimmune diseases-Chemotherapy. 2. Autoimmune diseases-
-Immunotherapy L Strand, Vibeke. IL Scott, David L.
[DNLM: I. Arthritis, Rheumatoid-therapy. 2. Autoimmune Diseases-
-therapy. 3. Antibodies, Monoclonal-therapeutic use.
4. Cytokines-antagonists & inhibitors. 5. Receptors, Antigen, T
-Cell-immunology. WE 346 N937 1997]
RC600.N68 1997
616.97' 8061-dc20
DNLMJDLC 96-18671
for Library of Congress CIP
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Copyright © 1997 by MARCEL DEKKER, INC. All Rights Reserved.
Neither this book nor any part may be reproduced or transmitted in any form or
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MARCEL DEKKER, INC.
270 Madison Avenue, New York, New York 10016
Current printing (last digit):
1098765432
To our families, without whom there would be
no place to go during both the good times and the bad.
We know we may often not be there in body,
but we are always with you in mind.
Preface
The idea for this book arose late one night, during a meeting, when the three of us
lamented the difficulties in finding a useful source for clinical information on the
novel therapies quickly coming into vogue in clinical research, and those just as
quickly becoming "passe." Although the biyearly "Biologics Meeting" publishes
proceedings, these are often released more than a year after the meeting and are
limited to those topics included in the program. Several basic science reviews
have discussed a variety of promising biological treatments, but are, of course,
limited to preclinical data in mice and rats. For this reason, we believe there is
great benefit to a compendium of potential new therapies in autoimmune diseases,
emphasizing the experience gained in humans, however preliminary. We have
focused on "innovative" therapies, including promising new pharmaceutical as
well as biological agents.
Our goal has been to make this book an invaluable single source for information
on newer interventions in the treatment of autoimmune diseases. Some of these
agents have yielded disappointing clinical results, or demonstrated toxicity, and
have passed on, without hope for approval. For others, data are still too prelimi-
nary to predict their future. ln the 14 months since this volume was conceived,
promising agents have come and gone, and we have come to appreciate the
challenging task we undertook. Data are often interim or just about to be pub-
lished, and therefore cannot be included in this book. Individual life cycle
v
vi Preface
changes, corporate politics, and other events beyond our control have thwarted
some of our best attempts to secure critical manuscripts. As a result, we have been
forced to overlook several promising agents. Nonetheless, the chapters in this
book reflect a great deal of patience and hard work on the part of the contributing
authors. If this volume serves a critical need, then a second edition may well
expand significantly the knowledge base presented in this edition.
Each of the innovative therapies discussed in this book has incrementally
helped us further understand the complicated pathophysiologic processes under-
lying autoimmunity, which have daunted mankind for hundreds of years. For
example, we now recognize the significant role TNFa: plays in the inflammatory
cascade, as was previously recognized for IL-1. And the clinical experiences with
each product have helped us better refine the process of "rational" drug develop-
ment, especially difficult when definitive treatments are lacking.
Although no treatment has yet offered a cure, we have made significant
progress. Since this book was conceived, two forms of Interferon~ have received
approval for the treatment of multiple sclerosis (MS). Clinical trials evaluating
three promising products are now under way in systemic lupus erythematosus
(SLE), a difficult disease to treat or even evaluate experimental treatment
therapies for. Some of the agents discussed in this book, as well as newer products,
are now being studied in psoriasis and/or Crohn's disease. An international col-
laboration is under way to develop a registry for autologous and allogeneic
stem-cell transplantation in patients with severe manifestations of autoimmune
disease such as SLE, MS, and systemic sclerosis. The first gene therapy trial in
arthritis has just been initiated.
There is every reason to believe that these innovative approaches, including
those discussed in this book, will yield better, more rational and well-tolerated
treatments for a variety of diseases heretofore inadequately addressed by our
therapeutic armamentarium.
Vibeke Strand
David L. Scott
Lee S. Simon
Contents
Preface v
Contributors xi
I. INTRODUCTION
1. The Evaluation of Biological Agents 1
Vibeke Strand and David L. Scott
II. CELLULAR TARGETED THERAPIES
2. Anti-CD5/Ricin A Chain Immunoconjugate Therapy in
Rheumatoid Arthritis 11
John]. Cush
3. Early Clinical Studies of IL-2 Fusion Toxin in Patients with
Severe Rheumatoid Arthritis, Recent-Onset Insulin-Dependent
Diabetes Mellitus, and Psoriasis 25
Thasia G. Woodworth and Karen Parker
4. Chimeric Anti-CD4 Antibody as a Potential Therapeutic Agent
for Rheumatoid Arthritis 41
Larry W. Moreland and William J. Koopman
vii
viii Contents
5. CD4 Monoclonal Antibody Therapy in Rheumatoid Arthritis 55
F. C. Breedveld
6. The Use of CE9.1, a Primatized Monoclonal Anti-CD4, in the
Treatment of Rheumatoid Arthritis 65
David E. Yocum, Alan M. Solinger, and John A. Lipani
7. CAMPATH-1H Therapy in Autoimmune Diseases 75
Richard A. Watts and John D. Isaacs
8. CAMPATH-1H in Rheumatoid Arthritis: United States
Experience 83
David E. Yocum and Jeffrey M. Johnston
III. CYTOKINE TARGETED THERAPIES
9. Interferon-Gamma in the Treatment of Rheumatoid Arthritis 95
Eric M. Veys, Herman Mielants, and Gust Verbruggen
10. Tumor Necrosis Factor Blockade in Rheumatoid Arthritis 107
Michael J. Elliott, Marc Feldmann, and Ravinder N. Maini
11. Human Anti-Tumor Necrosis 11<.,,,,,trn~-°'
AlltUIJ~oay CDP571, in Rheumatoid Arthritis 121
Ernest H. S. Choy and Gabriel S. Panayi
12. Clinical Experience with Recombinant Human Interleukin-I
Receptor Type I IL-lRI) in Patients with Rheumatoid
Arthritis 131
Richard M. Pope, Barbara Drevlow, Jennifer Capezio, Rosa lovis,
and Alan Landay
13. Treatment of Rheumatoid Arthritis with Soluble Tumor
Necrosis Factor Receptor 141
Gary R. Margolies, William J. Koopman, and Larry W Moreland
IV. ADHESION MOLECULE TARGETED THERAPIES
14. Treatment of Rheumatoid Arthritis with a Monoclonal Antibody
to Intercellular Adhesion Molecule-1 155
Arthur F. Kavanaugh and Peter E. Lipsky
Contents ix
V. POTENTIAL ANTIGEN-SPECIFIC THERAPIES
15. T-Cell-Receptor Peptide Therapy for Multiple Sclerosis 173
Arthur A. Vandenbark, Dennis N. Bourdette, Ruth H. Whitham,
and Halina Offner
16. T-Cell-Receptor Peptide Vaccination Studies in Rheumatoid
Arthritis 189
Louis W Heck, Larry W. Moreland, and William J. Koopman
17. Oral Tolerance for the Treatment of Autoimmune Disease 201
David A. Hafter and Howard L. Weiner
18. Oral Tolerance 221
David E. Trentham
19. Intravenous Immunoglobulin (IVIg) in the Treatment of
Autoimmune Diseases 235
Vibeke Strand and Martin L. Lee
VI. PURINE AND PYRIMIDINE SYNTHESIS INHIBITORS
20. Inhibitors of De Novo Nucleotide Synthesis in the Treatment
of Rheumatoid Arthritis 257
Robert l. Fox and Randall E. Morris
21. Leflunomide: A New Immunosuppressive Drug 287
David l. Scott and Vibeke Strand
VII. FUTURE DIRECTIONS
22. An Assessment of Novel Agents in the Treatment of the
Rheumatic Diseases 295
Vibeke Strand and Lee S. Simon
Index 301
Contributors
Dennis N. Bourdette, M.D. Acting Chief, Neurology Service, Portland
Veterans Affairs Medical Center, and Association Professor, Department of
Neurology, Oregon Health Sciences University, Portland, Oregon
F. C. Breedveld, M.D., Ph.D. Professor, Department of Rheumatology, Leiden
University Hospital, Leiden, The Netherlands
Jennifer Capezio, M.D. Department of Medicine, Northwestern University
Medical School, Chicago, Illinois
Ernest H. S. Choy, M.D., M.R.C.P. Lecturer in Rheumatology, Rheumatology
Unit, Division of Medicine, Guy's Hospital, London, England
John J. Cush, M.D. Associate Professor of Internal Medicine, Rheumatic
Diseases Division, University of Texas Southwestern Medical Center at Dallas,
Dallas, Texas
Barbara Drevlow, M.D. Department of Medicine, Northwestern University
Medical School, Chicago, Illinois
xi
xii Contributors
Michael J. Elliott, Ph.D., F.R.C.P Department of Clinical Immunology,
Kennedy Institute of Rheumatology, London, England
Marc Feldmann, Ph.D., F.R.C.P. Department of Cytokine Immunology,
Kennedy Institute ofRheumatology, London, England
Robert I. Fox, M.D., Ph.D. Member, Departments of Rheumatology and
Immunology, Scripps Clinic and Research Foundation, La Jolla, California
David A. Hatler, M. D. Director, Laboratory of Molecular Immunology, Center
for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts
Louis W. Heck, M.D. Associate Professor, Department of Medicine, University
of Alabama at Birmingham, Birmingham, Alabama
John D. Isaacs, M.B., B.S., M.R.C.P. MRC Research Fellow, Department of
Pathology, Addenbrooke's Hospital, Cambridge, England
Jeffrey M. Johnston, M.D. Senior Clinical Program Head, Rheumatology and
Immunology Clinic Research, Glaxo Wellcome, Inc., Research Triangle Park,
North Carolina
Arthur F. Kavanaugh, M.D. Associate Professor of Internal Medicine, Rheu-
matic Diseases Division, University of Texas Southwestern Medical Center at Dallas,
and Chief of Rheumatology, Dallas Veterans Affairs Medical Center, Dallas, Texas
William J. Koopman, M.D. Professor and Chairman, Department of Medicine,
University of Alabama at Birmingham, Birmingham, Alabama
Alan Landay, Ph.D. Department of Immunology/Microbiology, Rush-
Presbyterian-St. Luke's Medical Center, Chicago, Illinois
Martin L. Lee, Ph.D., C.Stat. Lecturer, School of Public Health, University of
California, Los Angeles, Los Angeles, California
John A. Lipani, M.D. Group Director, Inflammation and Tissue Repair,
SmithKline Beecham Pharmaceuticals, Collegeville, Pennsylvania
Peter E. Lipsky, M.D. Professor of Medicine and Microbiology, Department of
Internal Medicine, University of Texas Southwestern Medical Center at Dallas,
Dallas, Texas
Contributors xm
Rosa Lovis Research Technician, Department of Medicine, Northwestern
University Medical School, Chicago, Illinois
Ravinder N. Maini, M.B., B.Chin., F.R.C.P. Professor, Department of Clini-
cal Immunology, Kennedy Institute ofRheumatology, London, England
Gary R. Margolies, M.D. Lexington, Kentucky
Herman Mielants, M.D., Ph.D. Department of Rheumatology, Ghent Univer-
sity Hospital, Ghent, Belgium
Larry W. Moreland, M.D. Associate Professor of Medicine, Division of
Clinical Immunology and Rheumatology, Department of Medicine, University of
Alabama at Birmingham, Birmingham, Alabama
Randall E. Morris, M.D. Director, Transplantation Immunology, and Research
Professor, Department of Cardiothoracic Surgery, Stanford University School of
Medicine, Stanford, California
Halina Offner, Ph.D. Professor, Department of Neurology, Oregon Health
Sciences University, Portland, Oregon
Gabriel S. Panayi, M.D., Sc.D., F.R.C.P. ARC Professor of Rheuma-
tology, Rheumatology Unit, Division of Medicine, Guy's Hospital, London,
England
Karen Parker Manager, Department of Medical Communications, Seragen,
Inc., Hopkinton, Massachusetts
Richard M. Pope, M.D. Professor, Department of Medicine, Northwestern
University Medical School, Chicago, Illinois
David L. Scott, M.D. Reader in Rheumatology and Honorary Consultant
Rheumatologist, King's College School of Medicine and Dentristry, and King's
College Hospital, London, England
Lee S. Simon, M.D. Associate Professor of Medicine, Harvard Medical School;
Assistant to the Chairman, Department of Medicine, for Undergraduate Medical
Education; Assistant to the President, Deaconess Hospital, for Medical
Education; and Director of Rehabilitative Services, Deaconess Hospital, and
Dana-Farber Cancer institute, Boston, Massachusetts
xiv Contributors
Alan M. Solinger, M.D. Director, Clinical Therapeutics, IDEC Pharmaceuti-
cals Corporation, and Clinical Professor of Medicine, Division of Rheumatology,
Department ofinternal Medicine, University of California, San Diego, San Diego,
California
Vibeke Strand., M.D. Clinical Associate Professor, Division of Immunology,
Stanford University School of Medicine, Stanford, and Consultant in Clinical
and Regulatory Affairs, San Francisco, California
David E. Trentham, M.D. Chief, Division of Rheumatology, Beth Israel
Hospital, and Associate Professor of Medicine, Harvard Medical School, Boston,
Massachusetts
Arthur A. Vandenbark, Ph.D. Career Scientist, Department of Neuroim-
munology, Portland Veterans Affairs Medical Center, and Professor, Department
of Neurology, Oregon Health Sciences University, Portland, Oregon
Gust Verbruggen, M.D., Ph.D. Department of Rheumatology, Ghent Univer-
sity Hospital, Ghent, Belgium
Erk M. Veys, M.D., Ph.D. Department of Rheumatology, Ghent University
Hospital, Ghent, Belgium
Richard A. Watts, D.M., M.R.C.P. Senior Registrar, Rheumatology Research
Unit, Addenbrooke's Hospital, Cambridge, England
Howard L. Weiner, M.D. Co-Director, Center for Neurologic Diseases,
Brigham and Women's Hospital, Boston, Massachusetts
Ruth H. Whitham, M.D. Staff Physician, Neurology Service, Portland
Veterans Affairs Medical Center, and Associate Professor, Department of Neurol-
ogy, Oregon Health Sciences University, Portland, Oregon
Thasia G. Woodworth, M.D. Senior Associate Director, Department of
Experimental Medicine, Pfizer Central Research, Groton, Connecticut
David E. Yocum, M.D. Associate Professor and Director, Department of
Medicine, University of Arizona College of Medicine, Tucson, Arizona
I
Introduction
