Table Of ContentBiopharmaceutical
Drug Design
and Development
8 iopharmaceutical
Drug Design
and Development
Edited by
Susanna Wu-Pong
Virginia Commonwealth University, Richmond, VA
and
Yongyut Rojanasakul
West Virginia University, Morgantown, WV
Foreword by Joseph R. Robinson
Springer Science+Business Media, LLC
© 1999 Springer Science+Business Media New York
Originally published by Humana Press Inc. in 1999
Softcover reprint of the hardcover 1s t edition 1999
AII rights reserved. No part ofthis book may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or other
wise without written permission from the Publisher.
AII authored papers, comments, opinions, conclusions, or recommendations are those of the author( s ),
and do not necessarily reflect the views of the publisher.
This publication is printed on acid-free paper. ~
ANSI Z39 .48-1984 (American Standards Institute) Permanence of Paper for Printed Library Materials.
Source for cover illustration: Methods in Molecular Biology, Volume 62, Recombinant Gene Expression
Protocols, edited by Rocky S. Tuan: Fig. 3 from Chapter 20, "Expression ofExogenous Genes inXenopus
Oocytes, Eggs, and Embryos," by Koichiro Shiokawa, Chie Koga, Yazuru lto, and Mikihito Shibata.
Cover design by Patricia F. Cleary.
For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact
Humana at the above address or at any ofthe following numbers: Tel.: 973-256-1699; Fax: 973-256-
8341; E-mail: [email protected]; or visi t our Website: http:// humanapress.com
Photocopy Authorization Policy:
Authorization to photocopy items for interna) or personal use, or the interna\ or personal use of specific
clients, is granted by Springer Science+Business Media, LLC, provided that the base fee o fUS $10.00 per
copy, plus US $00.25
perpage, is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Dan vers, MA O1 923.
For those organizations that have been granted a photocopy Iicense from the CCC, a separate system of
payment bas been arranged and is acceptable to Springer Science+Business Media, LLC, The fee code
for users ofthe Trans actiona! Reporting Service is: [0-89603-691-X/99 $10.00 + $00.25].
10 9 8 7 6 5 4 3 2 1
Library of Congress Cataloging in Publication Data
Main entry under title:
Biopharmaceutical drug design and development/edited by Susanna Wu-Pong and Y ongyut
Rojanasakul.
p. cm.-
Includes index.
ISBN 978-1-4757-4644-0 ISBN 978-1-59259-705-5 (eBook)
DOI 10.1007/978-1-59259-705-5
\. Pharmaceutical biotechnology. 2. Gene therapy. 3. Biotechnology. 4. Molecular biology. 1.
Wu-Pong, Susanna. II. Rojanasakul, Yongyut.
[DNLM: 1. Biotechnology-methods. 2. Molecular Biology. 3. Genetic Engineering.
QH 453 M7186 1999]
RS380M65 1999
d615.07'.19-dc21
DNLM/DLC
for Library of Congress 99-53441
CIP
Foreword
New discoveries in biology are occurring at an incredible rate,
and with these discoveries arise nearly unimaginable opportunities
in every area of human existence. Imagine the excitement surround
ing the "penicillin project" and the subsequent rapid development of
anti-infective agents that took place in the 1940s and 1950s. Fast for
ward to the world today and our ability to treat life-threatening infec
tions. This is but one small piece in the present kaleidoscope of new
therapeutic agents. In fact, the world of science, biology, and medi
cine is changing so quickly that it is difficult for scientists and medi
cal practitioners to stay abreast of their fields and confidently
anticipate that their education and training will sustain them over a
three- to four-decade career without considerable continuing educa
tion and training. For the pharmaceutical scientist responsible for the
discovery and development of therapeutic agents based on advances
in biotechnology, it is imperative to quickly come up to speed and
stay at the forefront of developments, which is no easy task for those
not specifically trained in this area.
Biopharmaceutical Drug Design and Development, edited by
Susanna Wu-Pong and Yongyut Rojanasakul, cuts a potentially wide
swath in terms of its intended audience. It clearly is a primer for those
not trained in the area, or for those who wish to be brought into the
mainstream of drug discovery and development in the world of bio
technology. It is also a useful teaching text for such medical special
ties as pharmacy, nursing, and biotechnology.
Biopharmaceutical Drug Design and Development is an emi
nently readable book that fills a current void by bridging the highly
specialized world where new medicines are emerging from biotech
nology, as well as the more traditional small-molecule drug world.
The issues and concems associated with gaining approval, manufac-
V
vi Foreword
turing, and selling biotechnology products are, in many respects, con
siderably different from those encountered with their small-molecule
counterparts. The book also makes apparent the great difficulties en
countered in trying to target these molecules both spatially and tem
porally in the human body. All in all, Biopharmaceutical Drug Design
and Development gives a wonderful short history of the background
in biotechnology required to understand the field, as well as a view
of the issues and problems in the world of biotechnology product
development.
Joseph R. Robinson, PHD
School ofP harmacy
University of Wisconsin-Madison
Preface
In the four decades since the historical discovezy of the structure of
DNA by Watson and Crick, a revolution in biomedical technology has oc
curred. Previous to this momentous event, the use oftherapeutic quantities of
human proteins, the creation of novel protein and nucleic acid drugs, and the
delivezy oftherapeutic genes were only science fiction fantasies. Today, such
once-incredible technologies are either used daily in the treatment of dis
eases, including diabetes or heart attacks, or in developments slated for FDA
approval as early as the next decade. The technological hasis underlying these
remarkable advances is biotechnology, i.e., the use of cells, enzymes, DNA,
or other biologica! materials to produce a commercially useful product.
The rapid expansion of biotechnology since the 1950s has resulted in
the development of an array of technologies and methodologies that are ex
trernely sensitive, powerful, and accurate. On one hand, the explosion in the
field ofbiotechnology has produced 17 new, FDA-approved recombinant or
synthetic protein drugs since 1986, with hundreds more currently in clinical
trials. On the other hand, this explosion has resulted in a field whose technol
ogy can only remotely be understood by the population at large, and only
moderately conceptualized by even those with college or graduate degrees in
science. Therefore, the goal ofthis book is to provide students and profession
als in health care disciplines with a comprehensive account ofboth the neces
sary background information and ali the recent advances in medical
biotechnology needed to further the readers' awareness ofthis dynamic field.
Biopharmaceutical Drug Design and Development opens with an in
troduction to the biotechnology industry and a thorough review of the bio
chemical and biologica! principles underlying the specific
methods that comprise biotechnology. The structure ofDNA, RNA, and pro
teins are reviewed, in addition to the basic concepts of gene structure and
expression, cell membrane biology, and immunology. These topics are also
discussed in detail throughout the book to the degree that they are relevant to
understanding the principles and recent advances in biotechnology.
vii
viii Preface
Next, the basic tools used in biotechnology are reviewed in detail, in
cluding the scientific principles, methodology, uses, and limitations of each
method. These methods include recombinantDNAtechnology, the polymerase
chain reaction, monoclonal antibodies, and transgenic and gene transfer tech
nologies. Other relevant analytical techniques that apply to nucleic acid or
protein analysis are also discussed in this section.
In addition, Biopharmaceutical Drug Design and Development pro
vides an in-depth discussion of the application ofbiotechnology to medicine
and phannacy. The unique nature ofthe biotechnology-derived products (lruge,
hydrophilic, unstable nucleic acid or protein molecules; vaccines; cells;
transgenic plants or animals) has resulted in both new treatment opportunities
and a need for advances in several disciplines, including nucleic acid and
protein chemistry, drug design, the biochemical hasis of diseases, drug deliv
ery, fonnulation, scaleup, manufacturing, analysis, and quality control.
The drug approval process and the clinical applications oft hese unique
products are also addressed. The FDA objectives and requirements regarding
biologica! product testing in preclinical and clinical trials, as well as
postapproval considerations, are reviewed. Finally, for each approved and
investigational therapy, the rationale, indications for use, and special storage
and usage requirements are discussed in light of the unique nature of these
products.
Through this comprehensive, in-depth review and analysis ofbiotech
nology, we expect that our readers will gain a much deeper appreciation for
this remarkable field. Whether such an appreciation and understanding is
used to enhance one's research or one's clinical practice, or simply used to
raise awareness as a consumer ofbiotechnology-derived products, the phe
nomenal nature and enonnous potential ofthis technology will become clear
to the reader. Similarly, the hurdles that bar full realization of this technology
will also become apparent. Biopharmaceutical Drog Design and Develop
ment is intended to bring us closer to elucidating, prioritizing, and overcom
ing these hurdles as scientists, clinicians, and consumers in the health care
industry.
Susanna Wu-Pong
Yongyut Rojanasakul
Contents
Foreword ....................................................................................................... v
Preface ........................................................................................................ vii
Contributors ................................................................................................ xi
CH. 1. An Overview of Biotechnology
Susanna Wu-Pong ............................................................ 1
CH. 2. Basic Elements of Molecular Biology
Yongyut Rojanasakul ..................................................... 21
CH. 3. Tools for Molecular Analysis
Yongyut Rojanasakul and Sujatha Dokka ................... 3 7
CH. 4. Treatment Options
Susanna Wu-Pong .......................................................... 51
CH. 5. Viral Vectors for Gene Therapy
Kristoffer Valerie ............................................................ 69
CH. 6. Nonviral Gene Delivery
Frank L. Sorgi and Hans Schreier .............................. J07
CH. 7. Oligonucleotides and Ribozymes
Melanie Lysik and Susanna Wu-Pong ....................... 143
CH. 8. Design and Engineering of Proteins as
Therapeutic Agents
David R. Corey ............................................................. 187
CH. 9. Challenges and Issues in the Development of
F ormulations of Protein Pharmaceuticals
Steven J. Shire ............................................................... 205
CH. 1O . Protein Drug Delivery
Udaya B. Kompella ...................................................... 239
CH. 11. Protein Drug Manufacturing
Denny Lanfear, Randy Hassler, Karen Sitney,
Craig Curless, Sugu Patro, Larry Tsai,
and John Ogez ............................................................. 275
ix
Contents
X
CH. 12. Antibodies
Jerry T. Thompson and Kathleen D. Rigaut. .............. 329
CH. 13. Immunotherapy
Robert Tam ................................................................... 3 4 9
CH. 14. Product Deve1opment and New Drug Approva1
Victoria G. Hale ........................................................... 3 75
CH. 15. Therapeutic U se of Recombinant Proteins
Ronald M. Bukowski .................................................... 3 9 3
Index ................................................................................................. 429
