Biotechnology and Biopharmaceuticals: Transforming Proteins and Genes into Drugs

By Wiley

Biotechnology and Biopharmaceuticals: Transforming Proteins and Genes into Drugs, Second Edition addresses the pivotal issues relating to translational science, including preclinical and clinical drug development, regulatory science, pharmaco-economics and cost-effectiveness considerations. The new edition also provides an update on new proteins and genetic medicines, the translational and integrated sciences that continue to fuel the innovations in medicine, as well as the new areas of therapeutic development including cancer vaccines, stem cell therapeutics, and cell-based therapies.

• Language: English
• Publisher: Wiley
• Release date: Sep 19, 2013
• ISBN: 9781118659984

Book preview

Contents

CONTRIBUTORS

FOREWORD

PREFACE

PREFACE TO THE FIRST EDITION

ACKNOWLEDGMENTS

ORGANIZATION OF THE BOOK

USER AGREEMENT

Part I: TRANSFORMING PROTEINS AND GENES INTO DRUGS

1 INTRODUCTION TO BIOPHARMACEUTICALS

1.1. BACKGROUND AND SIGNIFICANCE

1.2. TRANSLATION OF BIOTECHNOLOGY FOR DEVELOPING BIOPHARMACEUTICALS

1.3. HISTORICAL PERSPECTIVE OF PHARMACEUTICAL BIOTECHNOLOGY

1.4. DISTINCTIONS BETWEEN CHEMICAL DRUGS VERSUS BIOPHARMACEUTICALS

1.5. SUMMARY

SUGGESTED READING

REFERENCES

2 DISTINCTIONS OF BIOLOGIC VERSUS SMALL MOLECULE PLATFORMS IN DRUG DEVELOPMENT

2.1. INTRODUCTION

2.2. TRANSFORMING NEW MOLECULES INTO DRUGS: THE DRUG DEVELOPMENT PROCESS

2.3. KEY DIFFERENCES BETWEEN BIOTECHNOLOGY AND CHEMICAL PRODUCTS

2.4. CURRENT TRENDS IN DRUG DEVELOPMENT

2.5. SUMMARY

REFERENCES

3 FINANCING BIOLOGIC DRUG DEVELOPMENT

3.1. INTRODUCTION

3.2. THE ROLE OF THE ORPHAN DRUG ACT

3.3. CLINICAL LEVERAGE STRATEGY IN ACCELERATING DRUG DEVELOPMENT

3.4. THERAPEUTIC TARGET CONSIDERATIONS

3.5. EVOLVING TRENDS

3.6. SUMMARY

REFERENCES

4 APPLICATION OF BIOTECHNOLOGY IN DRUG DISCOVERY AND EARLY DEVELOPMENT

4.1. INTRODUCTION

4.2. DATA MINING, MOLECULAR CLONING, AND CHARACTERIZATION

4.3. OPTIMIZATION OF CELL EXPRESSION SYSTEMS AND PRODUCT YIELD

4.4. MOLECULAR OPTIMIZATION

4.5. PROTEINS AND GENES AS TARGETS FOR DRUG DISCOVERY AND DEVELOPMENT

4.6. SUMMARY

SUGGESTED READING

REFERENCES

5 LARGE-SCALE PRODUCTION OF RECOMBINANT PROTEINS

5.1. INTRODUCTION

5.2. YIELD OPTIMIZATION IN GENETIC CONSTRUCTS AND HOST CELLS

5.3. LARGE-SCALE CULTIVATION OF HOST CELLS

5.4. DOWNSTREAM PROCESSING AND PURIFICATION

5.5. QUALITY ASSURANCE AND QUALITY CONTROL

5.6. SUMMARY

SUGGESTED READING

REFERENCES

6 CLINICAL PHARMACOLOGY, TOXICOLOGY, AND THERAPEUTIC DOSAGE AND RESPONSE

6.1. INTRODUCTION

6.2. CLINICAL PHARMACOLOGY AND TOXICOLOGY

6.3. DOSE AND THERAPEUTIC RESPONSE

6.4. DOSAGE FORM AND ROUTE OF ADMINISTRATION

6.5. SUMMARY

REFERENCES

7 CLINICAL EVALUATION AND REGULATORY APPROVAL AND ENFORCEMENT OF BIOPHARMACEUTICALS

7.1. INTRODUCTION: BIOLOGIC DRUG DEVELOPMENT AND APPROVAL

7.2. LICENSING OF BIOLOGICAL PRODUCTS

7.3. PRECLINICAL AND CLINICAL TESTING

7.4. FDA REVIEW AND APPROVAL PROCESS

7.5. REGULATORY ENFORCEMENT

7.6. GLOBALIZATION OF DRUG APPROVAL

7.7. SUMMARY

SUGGESTIONS FOR FURTHER READING

REFERENCES

8 PHARMACOECONOMICS AND DRUG PRICING

8.1. INTRODUCTION: PHARMACOECONOMICS

8.2. COST-EFFECTIVENESS: ASSESSING THE VALUE OF BIOPHARMACEUTICALS

8.3. THE COST OF DEVELOPING BIOPHARMACEUTICALS

8.4. PRICING BIOPHARMACEUTICALS

8.5. DRUG DEVELOPMENT INCENTIVES

8.6. ECONOMICS OF BIOSIMILARS

8.7. ECONOMIC IMPACT OF PERSONALIZED MEDICINE

8.8. SUMMARY AND FUTURE CHALLENGES

REFERENCES

Part II: THERAPEUTIC AND CLINICAL APPLICATIONS OF BIOPHARMACEUTICALS

9 ANTIBODIES AND DERIVATIVES

SECTION ONE

9.1. MOLECULAR CHARACTERISTICS AND THERAPEUTIC APPLICATIONS

REFERENCES

SECTION TWO

9.2. ANTIBODIES AND DERIVATIVES MONOGRAPHS LIST

9.3. ANTIBODIES AND DERIVATIVES MONOGRAPHS

10 HEMATOPOIETIC GROWTH AND COAGULATION FACTORS

SECTION ONE

10.1. MOLECULAR CHARACTERISTICS AND THERAPEUTIC APPLICATIONS

REFERENCES

SECTION TWO

10.2. HEMATOPOIETIC GROWTH AND COAGULATION FACTORS LIST

10.3. HEMATOPOIETIC GROWTH AND COAGULATION FACTORS MONOGRAPHS

11 CYTOKINES AND INTERFERONS

SECTION ONE

11.1. MOLECULAR CHARACTERISTICS AND THERAPEUTIC APPLICATIONS

REFERENCES

SECTION TWO

11.2. CYTOKINES AND INTERFERONS MONOGRAPHS LIST

11.3. CYTOKINES AND INTERFERONS MONOGRAPHS

12 HORMONES

SECTION ONE

12.1. MOLECULAR CHARACTERISTICS AND THERAPEUTIC APPLICATIONS

REFERENCES

SECTION TWO

12.2. HORMONES MONOGRAPHS LIST

12.3. HORMONES MONOGRAPHS

13 ENZYMES

SECTION ONE

13.1. MOLECULAR CHARACTERISTICS AND THERAPEUTIC APPLICATIONS

REFERENCES

SECTION TWO

13.2. ENZYMES MONOGRAPHS LIST

13.3. ENZYMES MONOGRAPHS

14 VACCINES

SECTION ONE

14.1. MOLECULAR CHARACTERISTICS AND THERAPEUTIC APPLICATIONS

REFERENCES

SECTION TWO

14.2. VACCINES MONOGRAPHS LIST

14.3. VACCINES MONOGRAPHS

15 OTHER BIOPHARMACEUTICAL PRODUCTS

15.1. OTHER BIOPHARMACEUTICAL PRODUCTS MONOGRAPHS LIST

15.2. OTHER BIOPHARMACEUTICAL PRODUCTS MONOGRAPHS

Part III: FUTURE DIRECTIONS

16 ADVANCED DRUG DELIVERY

16.1. INTRODUCTION

16.2. DRUG THERAPEUTIC INDEX AND CLINICAL IMPACT

16.3. ROUTES OF THERAPEUTIC PROTEIN ADMINISTRATION

16.4. PHYSIOLOGICAL AND MECHANISTIC APPROACHES

16.5. APPROACHES USING DEVICES

16.6. MOLECULAR APPROACHES

16.7. SUMMARY

REFERENCES

17 ADVANCES IN PERSONALIZED MEDICINE

17.1. INTRODUCTION TO INTERINDIVIDUAL VARIATION

17.2. HISTORICAL PERSPECTIVE ON PHARMACOGENETICS IN DRUG SAFETY AND EFFICACY

17.3. PHARMACOGENETICS IN DRUG DISPOSITION AND PHARMACOKINETICS

17.4. PHARMACOGENETICS IN DRUG EFFECTS AND PHARMACODYNAMICS

17.5. INDIVIDUALIZED GENE-BASED MEDICINE: A MIXED BLESSING

17.6. CURRENT AND FUTURE PROSPECTS OF PHARMACOGENETICS

17.7. SUMMARY

REFERENCES

18 GENE AND CELL THERAPY

18.1. OVERVIEW

18.2. GENERAL STRATEGIES IN GENE AND CELL THERAPY

18.3. GENE AND CELL THERAPY FOR SELECT MEDICAL CONDITIONS

18.4. GENE THERAPY IN RESEARCH, DEVELOPMENT, AND CLINICAL USE

18.5. STEM CELLS IN REGENERATIVE MEDICINE AND DIAGNOSTICS

18.6. SUMMARY

REFERENCES

19 INTEGRATION OF DISCOVERY AND DEVELOPMENT

19.1. OVERVIEW

19.2. INTEGRATION OF DISCOVERY AND DEVELOPMENT OF THERAPEUTIC CANDIDATES

19.3. GENOMICS: THE FIRST LINK BETWEEN SEQUENCES AND DRUG TARGETS

19.4. PROTEOMICS: FROM SEQUENCES TO FUNCTIONS

19.5. METABOLOMICS: METABOLIC PROFILE ELUCIDATION

19.6. INTEGRATING GENOMIC, PROTEOMIC, AND METABOLOMIC TOOLS TO ACCELERATE DRUG DEVELOPMENT

19.7. SUMMARY

REFERENCES

20 PHARMACOECONOMICS, OUTCOME, AND HEALTH TECHNOLOGY ASSESSMENT RESEARCH IN DRUG DEVELOPMENT

20.1. INTRODUCTION: HEALTH-CARE DECISIONS AND HEALTH OUTCOMES

20.2. INTEGRATION OF PHARMACOECONOMIC OUTCOME RESEARCH IN CLINICAL DRUG DEVELOPMENT

20.3. REGIONAL DIFFERENCES IN THE TYPE OF EVIDENCE AND VALUE DATA ESSENTIAL FOR HEALTH-CARE AND REIMBURSEMENT DECISIONS

20.4. BIOPHARMACEUTICAL COMPANY STRATEGIES

20.5. SUMMARY

20.6. ACKNOWLEDGMENTS

REFERENCES

21 FUTURE PROSPECTS

21.1. PROGRESS AND BENEFITS IN TRANSFORMING PROTEINS AND GENES INTO BIOPHARMACEUTICALS

21.2. GENOMIC INFORMATION IMPROVES SAFETY AND PRODUCTION COST OF BIOPHARMACEUTICALS

21.3. THE BUSINESS OF BIOPHARMACEUTICALS AND ECONOMIC IMPACTS

21.4. INFLUENCE OF BIOPHARMACEUTICALS ON PHARMACEUTICAL RESEARCH, DEVELOPMENT, AND THE DRUG INDUSTRY

21.5. PUBLIC–PRIVATE PARTNERSHIP IN FINANCIAL AND REGULATORY SUPPORT TO IMPROVE TRANSLATIONAL SUCCESS

21.6. BIOPHARMACEUTICALS AND PUBLIC HEALTH BENEFITS

21.7. PUBLIC PARTICIPATION AND INFLUENCE ON BIOPHARMACEUTICAL DEVELOPMENT

21.8. OUTLOOK

REFERENCES

Appendix I: DOSAGE FORM, PHARMACOKINETICS, AND DISPOSITION DATA

Appendix II: MOLECULAR CHARACTERISTICS AND THERAPEUTIC USE

Appendix III: NOMENCLATURE OF BIOTECHNOLOGY PRODUCTS

AIII.1 ANTIBODIES, AS IN MONOCLONAL ANTIBODIES

AIII.2 SOMATOTROPIN GROWTH HORMONES

AIII.3 INTERFERONS

AIII.4 COLONY-STIMULATING FACTORS (CSFS)

AIII.5 ERYTHROPOIETINS

AIII.6 INTERLEUKINS

Appendix IV: OTHER INFORMATION

Supplemental Images

INDEX

Copyright © 2013 by Wiley-Blackwell. All rights reserved

First edition © 2003 John Wiley & Sons, Inc.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data

Ho, Rodney J. Y.

    Biotechnology and biopharmaceuticals : transforming proteins and genes into drugs / Rodney J.Y. Ho and Milo Gibaldi. – 2nd ed.

        p. ; cm.

    Includes bibliographical references and index.

    ISBN 978-1-118-17979-6 (pbk.) – ISBN 978-1-118-65998-4 (epub) – ISBN 978-1-118-66037-9 (ePDF) – ISBN 978-1-118-66040-9 (emobi) – ISBN 978-1-118-66048-5

    I. Gibaldi, Milo. II. Title.

    [DNLM: 1. Biopharmaceutics. 2. Chemistry, Pharmaceutical. 3. Drug Design. QV 35]

    RS380

    615′.19–dc23

2013006645

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

This book is dedicated to

Lily, Beatrice, and Martin

CONTRIBUTORS

Ernest C. Borden, M.D.

Taussig Cancer Center, Learner Research Institute

Cleveland Clinic

Case Comprehensive Cancer Center

Cleveland, Ohio

Jenny Y. L. Chien, Ph.D.

Senior Research Advisor

Eli Lilly & Company

Lilly Corporate Center

Indianapolis, Indiana

Steve Elliott, Ph.D.

Amgen, Inc.

Thousand Oaks, California

Louis P. Garrison Jr., Ph.D.

Professor

Pharmaceutical Outcomes Research & Policy Program

School of Pharmacy

University of Washington

Seattle, Washington

Shiu-Lok Hu, Ph.D.

Professor

Departments of Pharmaceutics, Microbiology

Core Member, Regional Primate Research Center University of Washington

Seattle, Washington

Edward Kelly, Ph.D.

Research Assistant Professor

Department of Pharmaceutics

University of Washington

Seattle, Washington

Henry B. Koon, M.D.

University Hospitals

Case Comprehensive Cancer Center

Cleveland, Ohio

Graham Molineux, Ph.D.

Amgen, Inc.

Thousand Oaks, California

Sean M. Sullivan, Ph.D.

Executive Director

Pharmaceutical Sciences

Vical, Inc.

San Diego, California

Ramon V. Tiu, M.D.

Cleveland Clinic Taussig Cancer Institute

Case Comprehensive Cancer Center

Cleveland Clinic

Cleveland, Ohio

Roger L. Williams, M.D.

Chief Executive Officer

United States Pharmacopeia

Rockville, Maryland

FOREWORD

When asked for a foreword to the 2013 second edition of Ho and Gibaldi’s Biotechnology and Biopharmaceu­ticals; Transforming Proteins and Genes into Drugs, my first response was, who me? I have not actively engaged in the discovery and development of biopharmaceuticals, nor am I an active practitioner using these important medicines. Yet all of us, including me, are witnesses to the revolutionary advances in biopharmaceuticals chronicled in the second edition. So perhaps anyone could write this foreword and would be, as I am, honored to do so. My second question was, did I have to follow the typical pattern of writing a foreword that few would read and might even be considered boring? Or would it be possible to speak more directly, perhaps to an audience that would include the social media crowd? What if I were writing to the kids of today, and by kids I mean some of the readers of the second edition? Would it be possible to write something that would capture their fleeting attention as they peer myopically into small handheld screens? Well that is a challenge—how to capture the scientific and societal miracles of recent decades in 140 characters. As a start, I refer readers to the table of contents of the second edition, which (after suitable translation for the non-cognoscenti) not only speaks to drama, intrigue, and danger— the stuff of a Hollywood thriller—but also opens the door to fantastical visions of the future that are the stuff of science fiction.

The second edition consists of three parts: Part I, Transforming Proteins and Genes into Drugs—The Science and the Art; Part II, Therapeutic and Clinical Applications of Biopharmaceuticals—Proteins and Nucleic Acids; and Part III, Future Directions. Taken together, these sections demonstrate how rapidly the field of biotherapeutics has moved in the few years since the first edition of this book in 2003. The pace of revolution has clearly accelerated since elucidation of DNA in the mid-20th century as a biochemical computer disc-operating system, wherein plant and animal life appear as the discs are played. Each of the chapters in the second edition could be, and probably are, books in and of themselves, drawing together libraries of data, reports, and publications. For those who look at this information, it can be overwhelming. But the second edition moves beyond data and information and advances it in a way such that a good reader can be both knowledgeable and, if lucky, wise.

While the history that brings readers to the present Ho and Gibaldi’s second edition is longer, going back millennia, it is the revolutions of the last and current centuries that bring focus to this edition. The story of insulin is always part of this, and a key part of the insulin story is the idea of maintaining the potency of a biopharmaceutical through a common unitage, an idea which continues to this day and remains critically important. Some of these breakthroughs were societal in character, coming from nonscientists who can perhaps see the future as well as anyone. A key advance was the decision in 1962 by the U.S. Congress to amend the Food, Drug, and Cosmetic Act (FDCA) to include a requirement for efficacy. With a stroke of a presidential pen, the United States moved out of the dark into the light—the understanding that proof was needed that something good happened with a medicine in addition to associated risks. Continuing these societal revolutions were further legislative achievements, including the 1983 Orphan Drug Act, the 1984 Drug Price Competition and Patent Term Restoration Act, and now the 2009 equivalent for biopharmaceuticals, the Biologics Price Competition and Innovation Act signed into law in 2010. The 1984 legislation brought a focus on exposure measures, which are to be maintained over the life cycle of a medicine relative to the clinical trial material used to determine safety and efficacy. And this focus in turn brought about the need to consider consistency of these exposure measures relative to the therapeutic range for efficacy and toxicity in an individual. The 2009 legislation expanded the understanding of comparability and interchangeability. For a biopharmaceutical, issues of comparability arose in the context of pre- and postapproval change for a single manufacturer. These issues have now been extended to multiple manufacturers of biopharmaceuticals to include both biosimilar and interchangeable ­biosimilar medicines. Issues of interchangeability necessarily require an understanding of the importance of an individual’s dose–response relationship to allow what is termed switchability as opposed to ­prescribability. Given these important science constructs, Part I focuses on the challenges of commercializing a biotherapeutic, moving from financing challenges through key elements of the preclinical and clinical phases of drug development.

In Part II, overall approaches are expressed in terms of product classes, where clinical use of biopharmaceutical proteins are considered in terms of clinical effect and mechanism of action. Biomedical science revolutions are part of the fabric of the second edition. Coupled with the societal changes reflected in the FDCA—and in many ways driving them—are parallel revolutions in understanding the human genome and major advances in protein engineering. As a result, many new medicines will be biotherapeutics, with about 900 medicines in development. These medicines now can be grouped depending on what the molecules are (proteins, cells, genes) or what they do (hormones, cytokines and interferons, antibodies, enzymes, coagulation factors, vaccines). Not all of these 900 or so medicines will make it to market, but many will, and many more will advance as well.

The second edition considers many key issues in addition to the discovery, development, regulation, and use of biotechnology-based biopharmaceuticals. Personalized medicine and cost are part of these issues, as is quality. The FDCA speaks to identity, strength, quality, purity, and potency as means of assuring that a medicine is not adulterated. A subsidiary of the FDCA, the Public Health Service Act, speaks to strength, purity, and potency. Both can be summarized in the more overarching term quality. Biotherapeutics will be given for both acute and chronic illness and will also be used to maintain health. Issues of consistency in terms of the performance of a medicine have been with us for many years as part of the quality paradigm. My organization, the United States Pharmacopeial Convention, creates standards in official and authorized compendia to assure this continuing equivalence relative to clinical trial material throughout the life of any medicine, including a biopharmaceutical, during its time in the market. The science of equivalence (comparability) has advanced rapidly in recent years and is an especial challenge, requiring at times documentation and redocumentation of equivalence using clinical, nonclinical, and analytical approaches.

Testing for quality is summarized sometimes as determining whether an article is fit for purpose. Revolutions in diagnostics can determine whether we (humans) are fit for purpose and, if not, what can be done to rectify a deficiency, perhaps, increasingly, through administration of a biopharmaceutical. Shortly, if not now, next-generation DNA sequencing will allow us to observe our own biochemical (disc) operating ­systems, an understanding that would include how our own DNA is expressed genotypically or phenotypically through the rapidly advancing science of epigenetics. There is a saying: Know the truth, and the truth will make you free. Surely our own genetic truth will soon be available to all. But this knowledge, as well as tailored treatments, will come at a price. Most biotherapeutics are high-cost medicines that strain health-care budgets and simply are beyond the reach of even the most affluent in terms of out-of-pocket expenses. In Part III, the second edition considers these difficult issues, which once were a focus only for developing countries, sometimes termed the South. But we are all South now when it comes to paying for health care and sophisticated new medicines. Many might say that they wouldn’t want a miracle drug if it only gave a few more months of quality life and impoverished heirs. But families don’t always think that way—and they will do all they can for dear old dad or mom. The concluding chapters of Ho and Gibaldi’s second edition, though, signal hope as well as challenge, with emphasis on the value of a biotherapeutic medicine, expressed in pharmacoeconomic, outcome, and health technology assessments. With these instruments, scientific constructs may support access to good biotherapeutic medicines, including vaccines, for all. These and allied technologies are available increasingly throughout the world, leading to the possibility that miracle drugs may emerge in either the developed or developing world. Innovation increasingly knows no bounds, and associated science-based discovery, development, registration, and utilization constructs can rapidly disseminate into all parts of the world.

Ho and Gibaldi’s second edition brings it all together for us for biotechnology-based biopharmaceuticals. And who are we? We are 7 going on 8 billion primates, free to do almost anything we want, yet also capable of causing harm—to ourselves, to our fellow members of our species, and to our environment. At the end of the day, the miracles of biotherapeutics will be used. They will have names with quality attributes and labeling for use. A doctor will prescribe, physicians and pharmacists will work to optimize the dose, and a nurse or patient will administer them. They will heal and perhaps even cure in ways that we can scarcely imagine. And they will have adverse events. Long ago in a little town in Ohio, I had three aunts who lived longer and healthier lives thanks to insulin. I am living a longer and healthier life too as a result of good health care, including access to good medicinal care. The future is wide open, and a knowledge gate into this future is provided in Ho and Gilbaldi’s second edition. So to the social media crowd, here’s a short tweet—read this book in amazement and be ­prepared to benefit.

Roger L. Williams, M.D.

Chief Executive Officer

United States Pharmacopeia

Rockville, Maryland

PREFACE

Biotechnology, the application of biological molecules to mimic biological processes, has now proven to play a central role in the discovery and development of ­protein- and gene-based drugs. Since the first edition of Biotechnology and Biopharmaceuticals was published, the application of biotechnology to produce therapeutic proteins has vastly expanded the number of new drugs and their impact on human health. The list of biotechnology-based therapeutics has grown rapidly since recombinant insulin was approved in 1982. As of 2010, sales of the top protein therapeutic, Remicade, reached over $7.3 billion, which equates to an income of $20 million per day for the sponsoring companies. The 25 top-selling biopharmaceuticals generated $74.7 billion in 2010 for the worldwide health-care economy. With the complete human genome and the maturation in high-throughput technology for drug discovery, we continue to experience an exponential, unprecedented growth in the discovery of biotherapeutic modalities.

In the 10 years following publication of the first edition of this text, biotechnology and biotechnology products have matured significantly. From humble beginnings with technologies intended to replace endogenous proteins, innovations in biopharmaceutical technologies have propelled successful engineering of macromolecules and antibody therapeutics that are now brought to market at a faster pace than are small-­molecule drugs. These technologies are taking center stage in the development of biomolecule and small-­molecule drugs alike that are addressing medical conditions. These broad and expanding medical conditions include autoimmune diseases, cancers, cardiovascular disease, and infections. This expansion of biomedicines and their therapeutic impact has necessitated a complete rewrite of the first edition. Over the years, I have had the opportunity to visit and speak about biotechnology and a systems approach to drug targeting as well as nanomedicine around the world. In my visits, I have been privileged to learn how students and professionals as well as decision makers and the business community have found the topics useful and the presentation of the text helpful. Many have commented about the valuable insight gained from reading the text in a simple and easy-to-follow format. I appreciate their input and have made every effort to keep the text simple and minimize the use of jargon. As was the case for the first edition, the second edition of this book is intended as a single, comprehensive source of information, with insights into drug development, application, and the trajectory of biopharmaceuticals.

The studies of pharmacology and pharmaceutics as well as pharmacokinetics are integrated to establish and predict the relationship between clinical outcomes and the physical-chemical properties of traditional drugs and dosage forms. However, these principles often fail to accommodate the products of biotechnology. Over the past 20 years, the therapeutic application of protein-based drugs has provided a much fuller understanding of the intricacies and mechanisms of protein disposition and pharmacological actions. To fully appreciate the complexities of these macromolecules and their biological effects, one must understand the fundamental differences in drug design, dosage formulation, and time course of distribution to target tissues between protein-based drugs and small organic molecule drugs. As a consequence, new strategies have been developed to deliver protein-based drugs to therapeutic sites of action, and more will likely follow. This text also intends to highlight the integrated science and computer simulations used for predicting clinical outcomes of protein drugs and delivery systems.

Dr. Gibaldi and I initiated the task of creating the first edition of this book because we believed that not only established pharmaceutical scientists but also the broader public and professionals needed a fuller understanding of the creation and use of biopharmaceutical medicine. Also, students in training need to understand the principles underlying the discovery, development, and application of future drugs. An understanding and appreciation of these principles by health scientists, physicians, pharmacists, decision makers, other health-care providers, and policy makers will allow for informed decisions that improve the overall health care and well-being of patients. Integration of this knowledge into the context of cost-effectiveness of biopharmaceutical use will help executives and policy makers in their decision making. It is our belief that a single source of comprehensive information about biotechnology and biotherapeutics is needed to serve the interests of a large population of professionals. As with the first edition, transformation of biologic concepts to biopharmaceutical products are treated in the following ­perspectives: (1) the science and art of transforming pharmacology and biotechnology into therapeutic ­products, (2) the unique therapeutic aspects of different classes of biologics or macromolecules, and (3) the impact and prospect of cutting-edge biotechnologies and drug delivery systems. Together, all three perspectives presented are influencing medical practice and balancing health-care cost.

Rodney J. Y. Ho

PREFACE TO THE FIRST EDITION

The list of biotechnology-based therapeutics has grown rapidly since 1982 when the FDA approved the first recombinant biotech drug, insulin, for human use. The annual sales of several protein therapeutics have surpassed the billion dollar mark. With the completion of the primary DNA map for the human genome and the progress made in high-throughput technology for drug discovery, we are about to experience an explosive, never-before-seen growth in the development of therapeutic modalities. Biotechnology, the application of biological molecules and processes, will play a central role in the discovery and development of protein- and gene-based drugs. While there are books discussing various aspects of biotechnology, there is no single, comprehensive source of information available for health-care professionals.

The general principles of pharmacology and pharmaceutics have helped us to understand the relationship between clinical outcomes and the physical and chemical properties of traditional drugs and dosage forms. These principles, however, often do not apply to the products of biotechnology. The therapeutic application of protein-based drugs over the past 10 years has provided a much fuller understanding of the intricacies and mechanisms of the disposition in relation to pharmacological actions. To fully appreciate the complexities of these macromolecules and the corresponding biological effects, one must understand the fundamental ­differences in drug design, optimal dosage formulation, and time course of distribution to target tissues between protein-based drugs and small organic molecules. New strategies have been developed to deliver protein-based drugs, and more will follow.

We undertook the considerable task of creating this book because we believe established pharmaceutical scientists, as well as those in training, need to understand the principles underlying the discovery, development, and application of the drugs of the future. An understanding and appreciation of these principles by health scientists, physicians, pharmacists, and other health-care providers should allow informed decisions to improve the pharmaceutical care for patients. The ability to integrate this knowledge in the clinical setting is essential, particularly for the clinical pharmacologist and pharmacist. We also believe that a single source of comprehensive information about biotechnology is needed to serve the interests of a large population of professionals. This book considers biotechnology products from the following perspectives: (1) the integration of pharmacology and biotechnology with medical sciences, (2) the unique aspects of the applications of biologics or macromolecules as therapeutic agents, (3) the impact of biotechnology on medicine, and (4) the prospects of cutting-edge biotechnology and drug systems in shaping the future of medical practice.

Rodney J. Y. Ho and Milo Gibaldi

ACKNOWLEDGMENTS

I would first like to acknowledge the encouragement and long hours spent by the late co-author, Milo Gibaldi. His effort has made it possible to bring together research, development, regulation, and application of biotechnology products in an integrated book format. The time invested in developing and refining the presentation concepts and contents related to the complex biologic processes and methodologies used for creating biotechnology products have enriched this book. They have also allowed us to include additional insights that were not available to either of us alone. The same spirit was used in the assembly of this second edition. I appreciate the comments and input from students and professionals as well as decision makers and the business community. Their input has ensured that the text is simple with minimal jargon. Also, I am indebted to the works of many dedicated scientists and generous contributions of colleagues and clinicians around the world who continually strive to improve medical therapies. Without their foresight and creative research, this book would not have been possible. The stimulating discussions and support of colleagues from public institutions and the pharmaceutical industry kept the text on a realistic path and balanced without venturing into theoretical fantasies.

As this book is an outgrowth of many years of experience teaching pharmaceutical biotechnology to undergraduate, professional, and graduate students, I am indebted to individuals who have helped develop these topics over the years. These individuals include Kenneth E. Thummel, Danny D. Shen, Duane Bloedow, Shiu-Lok Hu, Edward Kelly, Cassian Yee, Sean D. Sullivan, Lou Garrison, Paul Carter, Perry Fell, Victor Wroblewski, Maurice Emery, Graham Molineux, Graham Jang, Dexi Liu, Paul Pearson, Dexiang Chen, Carol Collins, and Renta M. Hutabarat. I would like to acknowledge the University of Washington and Dean Baillie and their generous support of my sabbatical, which allowed me to work on this book project. The sabbatical was invaluable and allowed me to gather information and concentrate on writing. The continuous financial and resource support of the National Institutes of Health for a number of sponsored research programs through National Institutes of Allergy and Infectious Diseases; Heart, Lung, and Blood Institute; National Institute of Mental Health; National Center for Research Resources; National Institute of Neurological Disorders and Stroke; and National Institute of General Medical Sciences have also provided invaluable perspectives and insights on the biotechnology research enterprise and the evolving trends.

The preparation of Biotechnology and Biopharmaceuticals: Transforming Proteins and Genes into Drugs required the dedicated effort of many individuals. I would like to acknowledge the effort of John C. Kraft who spent hours to assist in editing the manuscript to improve readability, ensure timely receipt of manuscripts from cooperative, but very busy authors, and assemble the data. The effort of Wayne Chen, who spent hours in collecting data and helping with the assembly of the tables in the appendices, is invaluable. The committed efforts of the editorial and production staffs at John Wiley & Sons are also greatly appreciated.

Rodney J. Y. Ho

ORGANIZATION OF THE BOOK

This book, as with the first edition, is organized into three parts. Part I focuses on the process of taking a biological macromolecule, such as a natural protein found in minute quantities, from identification of its structure and function to a therapeutic agent that can be delivered safely and effectively to patients for a specific therapeutic indication. With the advancement of recombinant DNA technology and the rapid growth in automation efficiency and computing power, we now have many more drug targets than we can exploit to produce (recombinant or synthetic) drugs or pharmaceuticals that provide health benefits. Therefore, in this new age of biopharmaceuticals with a vast array of drug targets, it is increasingly important for drug industry decision makers, pharmaceutical scientists, and physicians to acquire the knowledge that has been gained from the experience of transforming biological macromolecules into drugs. This section highlights some of the key differences between the discovery and development of small-molecule drugs and high-molecular-weight biopharmaceuticals. Today, biopharmaceuticals are derived from peptides and proteins, which are often referred to as biologics, biomolecules, biotherapeutics, macromolecules, and protein therapeutics. In this book, we will use these terms interchangeably when referring to biopharmaceuticals.

For readers familiar with the biologic drug development process, and for clinicians who focus on the application of biopharmaceuticals, the chapters in Part II provide a brief overview of each class of macromolecule with respect to its physiological role and clinical application. The overview is followed by monographs for each FDA-approved, recombinantly derived biopharmaceutical, within each class of macromolecule. These monographs are organized as follows: (1) general description; (2) indications; (3) dosage form, route of administration, and dosage; (4) pharmacology and pharmaceutics (i.e., clinical pharmacology, pharmacokinetics, disposition, and drug interactions); (5) therapeutic response; (6) role in therapy; and (7) other clinical applications. Readers seeking pharmacokinetic information and additional details on molecular characteristics of biopharmaceuticals are directed to Appendices I and II.

Part III focuses on the future—advances that will enhance our ability to develop new and already-identified macromolecules into safe and effective biopharmaceuticals. Advanced drug delivery strategies aim to optimize selective drug exposure by targeting specific organs and tissues with physical-chemical and physiological approaches, amino acid sequence modification, and molecular redesign. These technologies are key to improving safety, efficacy, and increasing the limited bioavailability of macromolecules. This part also describes gene and cell therapies, which are strategies needed when traditional drug therapy is not suitable or effective. With the continued expansion of medication costs, the scientific community, general public, decision makers, and drug developers are using pharmacoeconomic tools to prioritize drug development programs. One of the chapters is devoted to discussing these pharmacoeconomic issues.

For potent drugs that produce severe toxicity in a small population of patients, but otherwise are safe and effective for the majority, laboratory-based genetic tests are being developed to identify the at-risk population. As our understanding of the relationship between pharmacological responses and genetic variations grows, it is important to understand how pharmacogenetic and other factors may allow pharmacists and physicians to consider the costs and benefits of individualized drug selection and dosage regimens. With newly automated analytical, robotic, and computational techniques, proteomics and genomics are accelerating drug discovery and predicting pharmacophores and perhaps pharmacokinetic properties. These techniques may allow scientists to minimize the number of candidate molecules that need to be synthesized or cloned. Some of these efforts have led to the chemical synthesis of active site mimics that are similar to classic small-molecule drugs.

This book concludes with a chapter on how ­biotechnology and scientific advances are being inte­grated by large and small biotechnology-driven and ­traditional pharmaceutical companies to accelerate drug discovery and development. At present the industry is almost universally incorporating biotech strategies as tools to accelerate drug development from concept to product, or it is fully engaging in developing biotherapeutic products. With proven public benefits and to improve clinical success rates, there is a growing trend in public and private partnerships in financing and regulatory support for translational research. It is interesting to note that public participation has continued to gain influence in the priority of which drugs are developed in the future.

To assist clinicians and researchers seeking infor­mation for specific biotherapeutics and their molecular properties, such information is compiled for easy access in the appendices. Appendix I provides dosage form and pharmacokinetic data, and Appendix II provides molecular characteristics and the therapeutic use of each biopharmaceutical. Naming conventions and nomenclature are assembled in Appendix III. Appendix IV provides additional information, such as RNA triplet codes, amino acid codes, and abbreviations.

USER AGREEMENT

The authors of Biotechnology and Biopharmaceuticals: Transforming Proteins and Genes into Drugs (referred to as Biotechnology and Biopharmaceuticals) have made conscientious and careful effort to provide accurate information on drug dosages and their use, including those outside of indication, that conform to the standards of professional practice that prevailed at the time of publication. However, standards and practices in medicine continue to change as new data become available. Therefore, each medical professional should consult additional sources, as needed. Before prescribing medications, the user is advised to check the product information sheet accompanying each drug to verify conditions of use and identify any changes in dosage schedule or contraindications, particularly if the agent to be administered is new and infrequently used, has a narrow therapeutic range, or suspected drug interactions.

Biotechnology and Biopharmaceuticals describes basic principles of biopharmaceutics and their use in drug therapy. The information provided is no substitute for individual patient assessment based upon the health-care provider’s examination of each patient and consideration of laboratory data and other factors unique to the patient. The book should be used as one of the tools to help the user make therapeutic decisions, bearing in mind that individual and unique circumstances may lead the user to reach decisions not presented herein.

NO WARRANTY. NEITHER Biotechnology and Biopharmaceuticals NOR ANY OTHER PARTY OR AUTHORS MAKE ANY WARRANTY OR REPRESENTATION, EXPRESSED OR IMPLIED, WITH RESPECT TO THE PRESENTED MATERIALS, WHICH ARE PRESENTED AS IS. ALL WARRANTIES ARE EXPRESSLY EXCLUDED AND DISCLAIMED, INCLUDING WITHOUT LIMITATION IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, AND ANY WARRANTIES ARISING BY STATUTE OR OTHERWISE IN LAW OR FROM COURSE OF DEALING, COURSE OF PERFORMANCE, OR USE OF TRADE. ANY STATEMENTS OR REPRESENTATIONS MADE BY ANY OTHER PERSON OR ENTITY ARE VOID. YOU ASSUME ALL RISK AS TO THE QUALITY, FUNCTION, PERFORMANCE, AND ACCURACY OF THE REPORTED MATERIALS.

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Some jurisdictions do not allow limitations on how long an implied warranty lasts, and some jurisdictions do not allow the exclusion or limitation of special, indirect, incidental, exemplary, or consequential damages, or the limitation of liability to specified amounts, so the above limitation and exclusion may not apply to you if prohibited by applicable law. You may also have other rights that vary from jurisdiction to jurisdiction. You agree that this Agreement shall not be subject to the United Nations Convention on Contracts for the International Sale of Goods.

If any provision of this Agreement is determined to be invalid or unenforceable under any applicable law, it shall be deemed omitted, and the remaining provisions shall continue in full force and effect. This Agreement may be modified only in writing authorized by Biotechnology and Biopharmaceuticals. Biotechnology and Biopharmaceuticals’ waiver of any right shall not constitute a waiver of that or any other right in the future. This Agreement shall be governed by and ­construed in accordance with the laws and in the state and federal courts of the State of Washington, USA. This Agreement constitutes the entire understanding between the parties with respect to the subject matter hereof, and all prior agreements, representations, statements, and undertakings, oral or written, are hereby expressly superseded and canceled.

Part I

TRANSFORMING PROTEINS AND GENES INTO DRUGS

The Science and the Art

Transformation of biotechnology and scientific discoveries into therapeutic products is a science and could be considered as an art. Biopharmaceutical products are mainly derived from peptides, nucleic acid polymers, and proteins. They are often referred to as biologics, biomolecules, biotherapeutics, macro­molecules, and protein therapeutics. In this book, we will use these terms interchangeably with the term biopharmaceuticals. The following eight chapters intro­duce the process of leveraging a series of discoveries in biological macro­molecules, including identification of their structures and elucidating their physiological roles for application as therapeutic agents. The path to prove a therapeutic molecule is safe and effective for patients is often complex and depends on science and more. With the advancement of recombinant DNA technology and the rapid growth in automation efficiency and computing power, many more drug targets are available to produce (recombinant or synthetic) drugs or pharmaceuticals. The discussions that follow document the knowledge and the experience gained from transforming biological macromolecules into drugs. The series of chapters highlight some of the key differences between the discovery and development of small-molecule drugs and high-molecular-weight biopharmaceuticals. The growing appreciation of the pivotal roles that public and private organizations play in supporting the enabling technologies through financial resources and leveraging all resources for drug development is an evolving art. Transformation of biomolecules into biopharmaceuti­cals includes build­ing capacity, evaluating therapeutic potential, and testing whether a molecule clears a defined set of tests in a test tube, in animals, and eventually in humans. The therapeutic molecules that clear the safety and efficacy evaluations and become endorsed by the US Food and Drug Administration are approved for human use. How the drug industry develops a price for a new therapy is an art. These integrated topics have proved to be increasingly impor­tant for decision makers, pharmaceutical scientists, and physicians in their practice.

1

INTRODUCTION TO BIOPHARMACEUTICALS

1.1. Background and Significance

1.2. Translation of Biotechnology for Developing Biopharmaceuticals

1.3. Historical Perspective of Pharmaceutical Biotechnology

1.4. Distinctions between Chemical Drugs Versus Biopharmaceuticals

1.5. Summary

    Biopharmaceuticals, otherwise known as the application of biomolecules as therapeutic products, have benefited from advances in the study of biology and biological interactions of simple and complex organisms including prokaryotes, eukaryotes, and mammalian systems. Basic discoveries and a greater understanding of ­biochemistry and biophysics have shed light on the abnormalities of the highly coordinated biological systems in humans that are related to disease symptoms. These discoveries have allowed for innovations to be made in the design and development of biopharmaceuticals for treating a wide range of human diseases. While biotechnology today is synonymous with advanced technologies, the technology of using biological molecules as therapeutics has been in existence since the 1800 s. Ever since elucidating that the human body is composed of specialized cells and proteins, exponential advances have provided enabling technologies that consistently produce high-quality proteins, antibodies, and peptides for pharmaceutical applications. Continued refinement and optimization of the production of recombinant macromolecules—enzymes, growth hormones, vaccines, and monoclonal antibodies—have fueled, and will continue to fuel, the growth and influence in overall drug development. When this text was first published in 2003, only a handful of biopharmaceuticals reached US $1 billion in annual sales. At the time of writing this second edition, the top-selling biopharmaceuticals reached US $7.3 billion, and the top 25 biopharmaceutical products generated US $74.7 billion in 2010. With over 200 biopharmaceutical products on the market, these achievements were possible because of the outstanding contribution of scientists and clinicians and their collective efforts to collaborate and integrate innovations into novel therapeutic products. This chapter defines the differences between small-molecule or traditional drugs and biologics or biotherapeutics—proteins, peptides, and biological materials—that are much larger molecules. A small change at the atomic level for a small-molecule drug typically leads to a new drug with a unique set of therapeutic and side effects, whereas a modification of amino acids (with multiple atomic modifications) on protein-based biotherapeutics, such as insulin and hepatitis B vaccine, retains a very similar therapeutic profile and clinical application. This chapter introduces in an easy-to-read level the growth in new biopharmaceuticals reaching the market, their therapeutic importance, and their overall contribution to health care. It is intended for students, health professionals, legislators, decision makers, and pharmaceutical researchers who want to learn about the science and business of biotechnology and its role in transforming biological discoveries into therapeutic products.

1.1. BACKGROUND AND SIGNIFICANCE

For most people, biotechnology is synonymous with "high-technology or advanced technology". However, the idea to use technology or products derived from biological molecules and processes for disease treatment is not new. Even before the discovery that the human body is composed of cells and proteins, humans were constantly being challenged by invading pathogenic microbes and other deadly infections. These real and perceived battlefields of disease necessitated innovations for developing curative medicines—biologically active therapeutic products now recognized as bio­pharmaceuticals. While biotechnology today is seen as the cutting edge of life sciences, the use of biological molecules as therapeutic agents or biologics has existed since the 1800 s. In fact, the word biotechnology can be traced back to the 1919 writing of Kark Erely in his 84-page publication entitled, "Biotechnologie der Fleisch-, Fett- und Milcherzeugung im landwirtschafttichen Gross-betrieb" (Bud 1989). The coining of the term biotechnologie or biotechnology by Erely was likely intended to describe the interaction of biology with technology, thus essentially implying inclusion of all biological and related technologies in product ­trans­formation. Today, the therapeutic products of ­bio­technologies, which are referred to as biologics or biopharmaceuticals, are central in providing hope and in making advances for treating human diseases ranging from infections, diabetes, and immune disorders to ­cancers. Biopharmaceuticals are derived from peptides and proteins, which are often referred to as ­biologics, biomolecules, biotherapeutics, macromolecules, and ­protein therapeutics. In this book, we will use these terms interchangeably when referring to bio­pharmaceuticals.

Figure 1.1. Time progression of milestones and overall impact on translation of biological molecules into therapeutic products. The discovery of protein, cell, bacteria, and Mendelian genetics in 1830–1900, and the innovative milestones in modern genetics and ­molecular engineering, provided the basis for exponential growth in the ability to identify, validate, and produce biological molecules for therapeutic applications. The accumulation and expansion of impact is represented on the x-axis. For color detail, please see color plate section.

The transformation of basic biological processes and endogenous proteins to biopharmaceuticals that treat disease and provide cures requires integration of scientific discovery and ingenuity into product development. The synthesis of biopharmaceuticals—proteins, peptides, and genetic materials— at a quality and quantity suitable for therapeutic use is a recent achievement. Some of the milestones and innovations pivotal to therapeutic achievements are highlighted in Figure 1.1. Clearly, basic knowledge about the DNA and the genetic code, different cells that make up ­tissues and organs, and protein synthesis and cellular mechanisms provided the foundation for exponential growth in biotechnology. Some of the significant ­biotechnology milestones and innovations are (1) recombinant DNA technology (procedures that join together, or recombine, DNA segments) to pro­duce human protein in foreign host cells (Cohen, Chang et al. 1973); (2) cell and fermentation technologies for large-scale protein production (Goeddel 1990); and (3) monoclonal antibody technologies (Kohler and Milstein 1975) that provide antibody ­therapeutics for treating immune or other disorders and cancers. These technological milestones have enabled transformation of biomolecules into ­biotherapeutics, which now impact health every day. Without transformational biotechno­logies, the health impacts of biotherapeutics such as ­proteins, antibodies, and enzymes (some of which are still available as tissue- or plasma-extracted products), would have been realized much later. Figure 1.1 also highlights the integration and potential impact due to the ever-expanding knowledge of biological processes and bioengineering. These scientific and engineering achieve­ments have allowed development and use of protein- and antibody-based therapies that require large doses (typically in milligrams or higher amounts) to impact patient health.

Translating biotechnology innovations into thera­peutic products requires investment by biopharmaceutical companies that focus on preclinical and clinical product development. While there are many entrepreneurial biotechnology start-up companies working on early-stage therapeutics, a majority of pioneering biotechnology companies, such as Genentech, Chiron, Cetus, and Immunex, that had success in developing therapeutic products, are eventually acquired by large pharmaceutical companies. This strategic acquisition of biotechnology companies has accelerated over the past 10 years. As a result, as shown in Table 1.1, Amgen is the only independent biotechnology company on the list. The other two companies, Genzyme and Biogen Idec, are part of or in the process of being integrated into large pharmaceutical companies. Table 1.1 also compares biotechnology and integrated biopharmaceutical companies and their 2010 revenue, market share, productivity as measured by revenue per employee, and investment in research and development (R&D). Although the total employee numbers are still relatively small, all of the listed biotechnology companies have grown to realize multi-billion dollar annual revenues, and their productivity is comparable to that of integrated biopharmaceutical companies ($632,000 vs. $506,000 per employee, respectively; Table 1.1). Biotechnology companies spend more than 20% (mean = 26%) of their revenue on R&D. This is well above the 11%–24% (mean = 16%) of revenue invested in R&D by integrated biopharmaceutical companies (Table 1.1). The difference is due, at least in part, to the high cost of biotechnology research and perhaps to the intellectual climate and culture at biotechnology-based companies compared to that at the more established companies.

TABLE 1.1. Comparison between a select list of established biotechnology and integrated biopharmaceutical companies with respect to revenue, market share, productivity, and research investments.a

TABLE 1.2. Top 25 biotechnology medicines based on reported worldwide sales.a

A survey of the 25 top-selling biotechnology drugs identified 21 products that achieved nearly US $1 billion or more in revenue for two consecutive years (Table 1.2). In 1999 (Ho and Gibaldi 2003), only four products achieved this milestone, and none were above the US $2 billion mark. For 2010, the annual revenue for each of the top six products—Remicade, Enbrel, Humira, Avastin, Rituxan, and Herceptin—reached more than US $5 billion each. The top product, Remicade, had worldwide sales of over $7.3 billion per year (equivalent to over US $20 ­million per day or US $610 million in sales per month). The sponsor companies listed in Table 1.2 include most of the major pharmaceutical companies. It is also interesting to note that generic versions of biotherapeutics (follow-on biologics) such as NeoRecormon, Genotropin, and Nor­ditropin also made it into the top 25 products, with annual sales reaching about US $1 billion. These follow-on biologics are marketed by integrated pharmaceutical companies. For the past 10 years, most large pharma­ceutical companies with little or no biological drug develop­ment programs have become central players in the development of biotechnology products by merging and acquiring start-up and successful biotechnology companies. As a result, there are hundreds of start-up companies, but the number of independent ­biotechnology-based companies is diminishing. The major pharmaceutical companies, which are now ­refer­red to as integrated biopharmaceutical companies, showcase biotechnology products as their top revenue generators in their respective annual reports. In essence, biotechnology drugs not only have a significant impact on health care, but also have become pivotal to the commercial vitality and success of the pharmaceutical industry. In 2010, the top 25 biotechnology drugs generated $74.7 billion within the health-care economy.

The availability of vast amounts of biological and genomic data coupled with exponential growth in computing power means that potential drug target numbers have increased exponentially. Thus, we are no longer limited by the ability to identify targets and clone recombinant macromolecules. The focus has now shifted to linking these molecules with disease symptoms. Nevertheless, we now have more targets than we can develop into pharmaceuticals. Therefore, drug candidate selection must be refined with the experience gained in using macromolecules as therapeutic agents. We must focus on drug candidates that will be safe and effective and also have desirable clinical pharmacokinetic profiles. Compounds that exhibit high-affinity binding to receptor targets but fail to penetrate target tissue or persist long enough to produce desirable biological responses cannot be considered for development as biopharmaceuticals.

Because the rate at which new biotechnology-based pharmaceuticals reach the market is no longer inhibited by the availability of novel targets, therapeutic importance and overall health-care cost now play central roles. Therefore, it is essential for health ­professionals, legislators, decision makers, and pharmaceutical researchers to understand the application of biotechnology to ­transform biological molecules and processes into pharmaceuticals and other therapeutic modalities.

In what follows, we will define biotechnology from the perspective of pharmaceuticals and then provide a historical overview of pharmaceutical biotechnology and a discussion of how macromolecules are named and used as therapeutic agents.

1.2. TRANSLATION OF BIOTECHNOLOGY FOR DEVELOPING BIOPHARMACEUTICALS

Biotechnology, like beauty, is in the eye of the beholder: a last hope for a patient with Alzheimer’s disease or cancer; an anathema to an environmentalist. Seeking a broad consensus, biotechnology is an integrated application of scientific and technical understanding of a biological molecule or process for developing a useful product. Biological processes of interest include cellular activities such as protein synthesis, DNA replication, transcription (DNA to RNA), protein processing, receptor–ligand interactions at cell surfaces, and fermentation of bacteria, yeast, and mammalian cells.

A broad definition of biotechnology includes beer and wine fermentation technology to produce distinctive beverages with commercial advantages, the identification of non-virulent variants to use as vaccines, genetic manipulation to coax bacteria to express metabolic enzymes that transform petroleum products into water-soluble forms for environmental clean-up, and the development of a recombinant, disease-resistant fruit or vegetable crop with prolonged freshness. Very often, biotechnology means commercialization of biological and life sciences by integrating discoveries from many disciplines, including microbiology, biochemistry, genetics, chemical biology, and bioengineering.

Currently, biotechnology is an integral component of many industries, in addition to pharmaceutical companies. This book will focus on the application of ­biotechnology to biological molecules and processes to develop pharmaceutical products or medicine and medical devices.

1.3. HISTORICAL PERSPECTIVE OF PHARMACEUTICAL BIOTECHNOLOGY

The application of biological processes to develop useful products is as old as Mendel’s pea experiment, conducted in 1866 (Mendel 1950) (Figure 1.1). As a result of the experiment, Mendel developed the principles of heredity and thereby formed the basis of modern genetics. Although the addition of the word biotech­nology to the dictionary did not occur until 1979, the fermentation technology we use today to produce recombinant proteins was first used in World War I to ferment corn starch (with the help of Clostridium acetobutylicum) (Weizmann and Rosenfeld 1937) and produce acetone for manufacturing explosives. Fermen­tation technology took on even greater importance after World War II with the development of antibiotics (Fleming 1929).

In the latter half of the 20th century, the revelation of protein structure, the elucidation of cell replication and protein synthesis, and the isolation of DNA replication enzymes, including restriction enzymes and polymerases, led to the rapid development of recombinant DNA technology. DNA replication technology in a test tube (in vitro) permitted cloning and expression of proteins and peptides in bacteria with much greater efficiency. This particular advance provided therapeutic candidate proteins that previously eluded efforts to isolate and harvest proteins just a few years earlier. At about the same time, in 1975, scientists developed monoclonal antibody (also known as hybridoma) technology (Kohler and Milstein 1975), which allowed for large-scale, reproducible preparation of purified, highly specific antibodies with monospecific binding sites (spanning 6–10 amino acids in length). This technology also allowed for the generation and use of monoclonal antibodies as a tool to characterize and purify proteins that would selectively bind to respective antibodies with high specificity. These tools for preparation and characterization of recombinant products have proved to be essential for developing macromolecules into therapeutic products.

The biotechnology milestones, presented in Figure 1.1, may not have by themselves permitted the rapid application of biotechnology to drug development, but in aggregate, they have led to the development of pharmaceutical products that could not have been realized without these technologies. Advances in technology make the process possible, accelerate it, or simply make products cost-effective and safer than the same material extracted from native tissues. A notable example is the development of an expression vector from a yeast plasmid (Valenzuela, Medina et al. 1982), which permitted mass production of the hepatitis B surface antigen for vaccine development and made economical manufacture of recombinant human insulin possible. Similar recombinant technology is still used today to produce recombinant papilloma virus particles (Zhou, Sun et al. 1991) as a vaccine (Gardasil) to prevent cervical cancer.

Almost all of the biopharmaceuticals available today are proteins or peptides. Of considerable importance among this array of products are monoclonal antibodies. These magic bullets became a reality with the marketing approval of Orthoclone (muromonab) in 1986. At ­present, monoclonal antibodies are the fastest growing category of biopharmaceuticals approved for therapeutic use. In fact, seven of the top-selling 2010 ­biotechnology drugs (with common names ending in "mab") are antibodies (Table 1.2). The ability to identify novel, potentially therapeutic proteins and peptides, like monoclonal antibodies, has advanced at such a rate that we are now limited by resources and the number of workers available to develop and demonstrate the clinical efficacy and safety of these candidates.

1.4. DISTINCTIONS BETWEEN CHEMICAL DRUGS VERSUS BIOPHARMACEUTICALS

Most small-molecule or chemical drugs typically exhibit a molecular weight of about 500 dalton (usually less than 1,000 dalton). Because of this small size, any chemical modification in a small-molecule drug can ­dramatically change its pharmacological activity and typically leads to new drugs for new uses or indications. For example, the addition of methyl groups at position 1, 3, and 7 of the natural substance xanthine produces the widely consumed compound caffeine; the addition of methyl groups at position 1 and 3 or 3 and 7 produces the bronchodilator, theophylline, or a related compound, theobromine(Figure 1.2). One would not substitute xanthine or caffeine for theophylline as a bronchodilator. By the same token, the addition of a hydroxy-methyl group to the anti-herpes simplex drug acyclovir results in ganciclovir, which has anticytomegalovirus activity (Figure 1.3). Acyclovir is widely used and considered much safer for treating herpes infection and preventing herpes reactivation, whereas ganciclovir is used only to treat cytomegalovirus (which is one of the herpes viruses) reactivation and exhibits significant side effects.

Figure 1.2. Molecular structures of xanthine, caffeine, theophylline, and theobromine. The addition of two or three methyl groups to specific locations on the natural substance xanthine can produce caffeine, theophylline, and theobromine.

One can find many more examples in which a subtle modification in a side chain leads to a new drug that produces a drastically different therapeutic or toxicological outcome. This is poignantly illustrated by the nonsedating antihistamine terfenadine (Seldane), which produces cardiotoxicity when given with certain drugs that inhibit its metabolism. For this reason, this product is no longer marketed, and it has been replaced by its safer but no less effective carboxylic oxidative metabolite fexofenadine (Allegra), which substitutes the methyl side chain with carboxylic acid (Figure 1.3). These examples clearly demonstrate that a small change—methylation, carboxylation, or hydroxylation—in a small-molecule chemical drug leads to a new chemical entity with a distinctly different therapeutic and toxicology profile.

On the other hand, biopharmaceuticals based on natural proteins and peptides are often called by the same name as the natural material despite differences in one or more amino acid residues. In other words, a small change does not lead to a new biotherapeutic product. For example, insulin, which is used to treat diabetes, has several variants that are approved for human use. Insulin contains two A and B polypeptide chains linked together by two disulfide bridges to assume a biologically active conformation (Figure 1.4). Compared with endogenous or recombinant human insulin, insulin extracted from beef tissue exhibits threonine→alanine and isoleucine→valine substitutions at positions 8 and 10 of the insulin A chain, respectively, whereas insulin extracted from pork tissue contains a threonine→alanine substitution at position 30 of the insulin B chain (Table 1.3). Yet, both pork and beef insulins have been used successfully to treat diabetes. Although trade names may differ, all the insulins, including those that are modified to produce more desirable pharmacokinetic and disposition profiles, such as insulin-lispro, insulin-glargine, insulin-glulisine, and insulin-aspart, are still known as insulins by physicians and researchers alike. All of these variants of insulin are used for the same treatment indication—to control blood glucose—and are efficacious as long as the dose and dosing frequency are determined on a product-by-product basis.

The same name is also used for some vaccines that differ in potency. As shown in Table 1.4, the two approved vaccines against hepatitis B, Recombivax HB and Engerix-B, are both known as (recombinant) hepatitis B vaccine. However, the dose and volume required to produce a satisfactory immune response are different for each product and age group. Despite these differences, physicians use the two vaccines interchangeably. The difference in dose between the two may be due to sequence and production variations of the recombinant proteins used to prepare the vaccines. When used as directed, the vaccines are therapeutically equivalent in terms of their ability to induce antibodies that protect vaccinated individuals from hepatitis B virus infection.

Figure 1.3. Molecular structures of acyclovir, ganciclovir, fexofenadine, and terfenadine. Modification of a side chain changes ­acyclovir to ganciclovir and terfenadine to fexofenadine.

Figure 1.4. Schematic presentation of insulin A and B chains and the amino acid sequence of human insulin. The clear circles with black letters indicate where sequence modifications are made to provide insulin derivatives with varying rates of therapeutic response. The dotted circles represent where amino acid (Arg) additions are made to provide sustained release of insulin from the injection site.

TABLE 1.3. Sequence variation between some insulins available for human administration.

TABLE 1.4. Comparison of recombinant hepatitis B vaccines dose recommendations.

1.5. SUMMARY

Pharmaceutical biotechnology is a process of translation and integration of biological and life science discoveries to produce biologics and therapeutic products. It has had great impact on human health. Today, biopharmaceuticals are central to treatments of infections, diabetes, immune disorders, and cancers. In 2010, the top revenue-generating biotechnology product reached $7.3 billion, and collectively,