Table Of ContentTUMOR TARGETING IN CANCER THERAPY
CANCER DRUG DISCOVERY AND DEVELOPMENT
Beverly A. Teicher, Series Editor
Tumor Targeting in Cancer Therapy, edited by Michel Page, 2002
Chemoradiation in Cancer Therapy, edited by Hak Choy, 2002
Targets for Cancer Chemotherapy: Transcription Factors and Other Nuclear
Proteins, edited by Nicholas B. La Thangue and Lasantha R. Bandara, 2002
Endocrine Therapy in Breast and Prostate Cancer, edited by V. Craig Jordan
and Barrington J. A. Furr, 2002
Tumor Models in Cancer Research, edited by Beverly A. Teicher, 2002
Tumor Suppressor Genes in Human Cancer, edited by David E. Fisher, 2001
Matrix Metalloproteinase Inhibitors in Cancer Therapy, edited by Neil J.
Clendeninn and KrzysztoJ Appelt, 2001
Farnesyltransferase Inhibitors in Cancer and Cardiovascular Therapy, edited
by Saiä M. Sebti and Andrew D. Hamilton, 2001
Platinum-Based Drugs in Cancer Therapy, edited by Lloyd R. Kelland and
Nicholas P. Farrell, 2000
Apoptosis and Cancer Chemotherapy, edited by John A. Hickman
and Carotine Dive, 1999
Signal Transduction and Cell Cycle Inhibitors in Cancer Therapy,
edited by J. Silvio Gutkind, 1999
Antifolate Drugs in Cancer Therapy, edited by Ann L. Jackman, 1999
Antiangiogenic Agents in Cancer Therapy, edited by Beverly A. Teicher, 1999
Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials,
and Approva~ edited by Beverly A. Teicher, 1997
Cancer Therapeutics: Experimental and Clinical Agents, edited by
Beverly A. Teicher, 1997
TUMOR T ARGETING
IN CANCER THERAPY
Edited by
MICHEL PAGE, PhD
0/
Department Medical Biology,
0/
Faculty Medicine, Universite Lava/,
Sainte-Foy, Quebec, Canada
~
~ Springer Science+Business Media, LLC
© 2002 Springer Science+Business Media New York
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Library of Congress Cataloging-in-Publication Data
Tumor targeting in cancer therapy/edited by Michel Page.
p.;cm.-(Cancer drug discovery and development)
ISBN 978-1-61737-251-3 ISBN 978-1-59259-167-1 (eBook)
DOI 10.1007/978-1-59259-167-1
1. Cancer-Immunotherapy. 2. Cancer-Chemotherapy. 3. Drug targeting.1. Page,
Michael. 11. Series.
[DNLM: . Neoplasms-immunology. 2. Antibodies, Neoplasm-therapeutic use. 3.
Antineoplastic Agents-therapeutic use. 4. Drug Delivery Systems. 5.
Neoplasms-therapy. QZ 266 T9265 2002]
RC271.I45 T86 2002
616.99'406---dc21
2001051657
PREFACE
The purpose ofTumor Targeting in Cancer Therapy is to describe both experimental and
clinical applications of antibodies for targeting tumors. Drug targeting has gone a long way
since the initial concept of "magie bullets" was developed by Paul Ehrlich at the beginning
of the 20th century.
Twenty-five years after their discovery and after many years of failure to bring them
to the bedside for therapeutic uses, monoclonal antibodies are now in a renaissance phase,
both clinically and commercially.
Monoclonal antibodies are theoretically ideal for the therapeutic area with all the
required properties such as an extreme specificity and binding affinity that could be
adjusted as needed, low cost commercial production, and a potential to be tailored to
specific needs such as they could be made to fix, complement, be monomers, dimers, to be
toxic or nontoxic; they could also be made to fix the same antigen on both arms of the
antibody or different ones as needed. They have limitless applications in the therapeutic
area.
When Ehrlich proposed the concept of magie bullets for the treatment of cancer, he
probably had in mind drug targeting with polyclonal antibodies, but with the development
of other fields in cancer therapy and in biotechnology, the concept has now been applied to
radioimmunotherapy, radioimmunodetection, therapy with cytotoxic antibodies,
immunotoxins, enzyme-prodrug immunotherapy, immunotherapeutics with fusion proteins,
and a whole range of applications that are discussed in Tumor Targeting in Cancer Therapy.
Presently, more than 15 % of all drugs in development are deri ved from the monoclonal
antibody technology. The drug industry has entered a new era, and products derived from
biotechnology, and more specifically antibodies, are now applied to heart disease, can
cer, and infectious diseases.
The immunogenicity of monoclonal antibodies for humans, which was for a long
time a stumbling block, and the short half-life in circulation are now better understood
and controlled by various strategies such as chimerization, phage display technology,
and humanization. These technologies have also permitted the affinity of monoclonal
antibodies to be increased to the picomolar range. It must be remembered, however, that
for cancer therapy the high affinity antibody is not always the best candidate.
Many pharmaceutical companies have built on these technologies, and the number of
clinical trials with monoclonal antibodies is still increasing.
Tumor Targeting in Cancer Therapy is intended for scientists, clinicians, and phar
maceutical investigators in cancer immunology and cancer therapeutics. It covers the
various aspects of targeted cancer therapy, from fundamentals to biodistribution and clini
cal applications. The contributors come from academic institutions, government, the drug
industry, and the biotechnology industry.
Each chapter covers a specific aspect of targeting without too many technical details.
Tumor Targeting in Cancer Therapy is not an accumulation of scientific papers on the
subject, but instead offers state-of-the-art reviews on each topic.
For graduate students and for new scientists in the field, the first chapter gives a
complete review on the subject. It also gives the necessary information to be able to
evaluate technologies available to start new projects, and for teaching cancer therapeutics
and immunology.
v
vi Preface
It was a pleasure to edit this book and I thank all the authors for their collaboration. I
also leamed as an editor new reasons for not respecting the deadline. Many that I had
never used before. I thank you for writing these exceptional scientific papers and I wish
all authors and readers good luck in their research.
Michel Page, PhD
CONTENTS
Preface ............................................................................................................................ v
Contributors ................................................................................................................... ix
I.
PART A REvIEw
1 The Current Status of Tumor Targeting: A Review .......................... 3
Tarunendu Ghose
2 Clinical Applications of Targeted Therapeutics ............................ 79
Tarunendu Ghose
11.
PART T ARGETING TUMORS WITH DRUG ANTIBODY CONJUGATES
3 Targeting the CD22 Receptor with RNA Damaging Agents ...... 109
Huaitian Liu, Dianne L. Newton, Hans 1. Hansen,
Stanislaw M. Mikulski, David M. Goldenberg,
Edward A. Sausville, and Susanna M. Rybak
4 The Development of Liposomes for Enhanced Delivery
of Chemotherapeutics to Tumors ............................................. 119
Paul Tardi, Ludger fckenstein, Marcel Bally,
and Lawrence Mayer
5 Overcoming Multiple Drug Resistance
with Anti-Pgp Carrier ............................................................... 137
Brigitte Page and Michel Page
6 Targeting with Transferrin ............................................................ 151
Mandip Singh
7 Synthesis and Evaluation of Paclitaxel Immunoconjugate
with Antitumor Activity In Vitro ............................................. 165
lairo laime Correa and Michel Page
8 The Use of Drug-Monoclonal Antibody Conjugates for the
Treatment of Cancer ................................................................. 179
Geoffrey A. Pietersz and fan F. C. McKenzie
111.
PART T ARGETING TUMORS WITH ANTIBODIES
9 Targeting Vascular Endothelium with Antibodies ....................... 199
Przemek Twardowski and Kim Margolin
10 Targeting B-Cell Non-Hodgkin's Lymphoma
with Monoclonal Antibodies .................................................... 211
Christian Buske and W. Hiddemann
11 From Bench to Bedside: Development oJ Rituximab
(Rituxan ®), A Monoclonal Antibody Jor the Therapy
oJ Non-Hodgkin 's Lymphoma .................................................. 225
Roland Newman
12 Mylotarg: The First Antibody-Targeted Chemotherapy Agent ... 239
Philip R. Hamann and Mark S. Berger
vii
viii Contents
P"ART IV. T ARGETING TUMORS WITH RADIOIMMUNOCONJUGATES
13 188Rhenium_ Labeled Trisuccin-LlCH2HuCC49
as a Radioimmunotherapy Model in Nude Mice ..................... 257
Ahmad Safavy and Donald 1. Buchsbaum
PART V. T ARGETING TUMORS WITH IMMUNOTOXINS
14 General Approach for Targeting Toxins ...................................... 279
Manish Monga, Richard A. Messmann,
and Edward A. Sausville
15 Antibody-Toxin Conjugates: Chemistry of Coupling
and Purification ........................................................................ 289
Silvana Canevari, Maria Ines Colnaghi, Luigi Cattel,
and Franco Dosio
16 Shiga-Like Toxins as Targeted Anticancer Agents ..................... 307
Paul LaPointe and lean Gariepy
PART VI. T ARGETING TUMORS WITH ANTIBODY -ENZYME CONJUGATES
(ADEPT)
17 Antibody-Directed Enzyme Prodrug Therapy
with Carboxypeptidase G2: Clinical Studies ........................... 321
Kenneth D. Bagshawe
PART VII. PHOTODYNAMIC THERAPY
18 Photodynamic Therapy: Targeting Cancer Cells
with Photosensitizer-Bioconjugates ......................................... 329
Cynthia M. Allen, Wesley M. Sharman,
and lohan E. van Lier
19 Tumor Targeting Using PEG-m-THPC for Photodynamic
Therapy in a Rat Ovarian-Cancer Model ................................. 363
Rene Hornung
PART VIII. T ARGETING TUMORS WITH MAGNETIC DRUGS
20 Targeting Tumors with Magnetic Drugs ..................................... 379
Andreas S. Lübbe, Christian Bergemann,
and Christoph Alexiou
PART IX. PRINCIPLES AND TECHNIQUES IN T ARGETING
21 Internalization of Antibodies ........................................................ 391
lairo laime Correa
22 Bioconjugation and Biodistribution ............................................ .411
Francesco M. Veronese and Paulo Caliceti
23 Principles of Antitumor Targeting of Cytotoxic Drugs ............... 431
Gene M. Dubowchik
24 Targeting by Antibody or Ligand: Wh ich Is Better? ................... 449
Douglas A. Lappi
Index ........................................................................................................................... 459
CONTRIBUTORS
CHRISTOPH ALEXIOU • Klinikum Rechts der Isar, Munich, Germany
CYNTHIA M. ALLEN • Institute of Biological Sciences, National Research Council,
Ottawa, Ontario, Canada
KENNETH D. BAGSHAWE· Emeritus Professor of Medical Oncology, Imperial College
School of Medicine, Charing Cross Campus, London, UK
MARCEL BALLY • Department of Advanced Therapeutics, BC Agency, Celator
Technologies Inc., Vancouver, British Columbia, Canada
CHRISTIAN BERGEMANN • Chemicell Inc., Berlin, Germany
MARK S. BERGER· Clinical Research and Development, Wyeth-Ayerst Research,
Collegeville, PA
DONALD J. BUCHSBAUM • Department of Radiation Oncology, Division of Radiation
Biology, University of Alabama at Birmingham, Birmingham, AL
CHRISTIAN BUSKE • Department of Medicine III, Ludwig-Maximilians University,
Munich, Germany
PAULO CALICETI • Department of Pharmaceutical Sciences, University of Padua, Padova,
Italy
SILVANA CANEVARI· Department of Experimental Oncology, Istituto Nazionale
Tumori, Milan, Italy
LUIGI CATTEL· Department of Drug Science and Technology, Turin, Italy
MARIA INEs COLNAGHI • Department of Experimental Oncology, Istituto Nazionale
Tumori, Milan, Italy
JAIRO JAIME CORREA· Department of Medical Biology, Faculty of Medicine,
Universite Laval, Ste Foy, Quebec, Canada
FRANCO DOSIO· DISCAFF, Novara, Italy
GENE M. DUBOWCHIK • Bristol-Myers Squibb Pharmaceutical Research Institute,
Wallingford, CT
JEAN GARIEPY • Department of Medical Biophysics, University ofToronto and The
Ontario Cancer Institute, Princess Margaret Hospital, University Health Network,
Toronto, Canada
T ARUNENDU GHOSE • Professor Emeritus in Pathology, Dalhousie University, Halifax,
Nova Scotia, Canada
DAVID M. GOLDENBERG • Garden State Cancer Center, Belleville, NI
PHrLlP R. lIAMANN • Oncology/Chemical Sciences, Wyeth-Ayerst Research, Pearl River, NY
HANs J. HANSEN • Immunomedics Inc., Morris Plains, NI
W. HIDDEMANN • Department of Medicine III, Ludwig-Maximilians University,
Munich, Germany
RENE HORNUNG • Beckman Laser Institute and Medical Clinic, University of Califomia,
Irvine, CA; Department of Obstetrics and Gynecology, University Hospital
Zurich, Zurich, Switzerland
LUD GER IcKENSTEIN • Department of Advanced Therapeutics, BC Agency, Celator
Technologies Inc., Vancouver, British Columbia, Canada
PAUL LAPOINTE • Department of Medical Biophysics, University ofToronto and The
Ontario Cancer Institute, Princess Margaret Hospital, University Health Network,
Toronto, Canada
ix
x Contributors
DOUGLAS A. LAPPI • Advanced Targeting Systems, San Diego, CA
HUAITIAN LIU • Developmental Therapeutics Program, Division of Cancer Treatment
and Diagnosis, NCI-FCRDC, National Institutes of Health, Frederick, MD
ANDREAS S. LÜBBE· Cecilien-Klinik, Bad Lippspring, Germany
KIM MARGOLIN· Department of Medical Oncology and Therapeutics Research, City
of Hope National Medical Center, Duarte, Canada
LAWRENCE MAYER· Department of Advanced Therapeutics, BC Agency, Celator
Technologies Inc., Vancouver, British Columbia, Canada
IAN F. C. McKENZIE • The Austin Research Institute, Heidelberg, Victoria, Australia
RICHARD A. MESSMANN • Developmental Therapeutics Program, Division of Cancer
Treatment and Diagnosis, National Cancer Institute, Bethesda, MD
STANISLAW M. MIKULSKI· Alfacell Corp., Bloomfield, Ni
MANISH MON GA • National Cancer Institute-Medicine Branch, Bethesda, MD
ROLAND NEWMAN • IDEC Pharmaceuticals, San Diego, CA
DIANNE L. NEwToN • SAIC Frederick, National Cancer Institute-Frederick Cancer
Research and Development Center, Frederick, MD
BRIGITTE PAGE· Biotechlab, Quebec, Canada
MICHEL PAGE • Department of Medical Biology, Faculty of Medicine, Universite
Laval, Sainte-Foy, Quebec, Canada
GEOFFREY A. PIETERSZ • The Austin Research Institute, Heidelberg, Victoria, Australia
SUSANNA M. RYBAK • Developmental Therapeutics Program, Division of Cancer
Treatment, and Diagnosis, National Cancer Institute-Frederick Cancer Research
and Development Center, National Institutes of Health, Frederick, MD
AHMAD SAFAVY· Division of Radiation Biology, Department of Radiation Oncology,
University of Alabama at Birmingham, Birmingham, AL
EDWARD A. SAUSVILLE • Developmental Therapeutics Program, Division of Cancer
Treatment, and Diagnosis, National Cancer Institute-Frederick Cancer Research
and Development Center, National Institutes of Health, Frederick, MD
WESLEY M. SHARMAN • Department of Nuclear Medicine and Radiobiology, Faculty
of Medicine, Universite de Sherbrooke, Sherbrooke, Quebec, Canada
MANDIP SINGH • College of Pharmacy, Florida A & M University, Tallahasee, FL
PAUL TARDI· Celator Technologies Inc., Vancouver, British Columbia, Canada
PRZEMEK TWARDOWSKI· Department of Medical Oncology and Therapeutics
Research, City of Hope National Medical Center, Duarte, Canada
JOHAN E. VAN LIER • Department of Nuclear Medicine and Radiobiology, Faculty
of Medicine, Universite de Sherbrooke, Sherbrooke, Quebec, Canada
FRANCESCO M. VERONESE • Department of Pharmaceutical Sciences, University of Padua,
Padova, Italy
