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ANTIBODY THERAPEUTICS Pharmacology and Toxicology: Basic and Clinical Aspects Mannfred A. Hollinger, Series Editor University of California, Davis Forthcoming Titles Anabolic Treatment for Osteoporosis, James F. Whitfield and Paul Morley Antisense Oligodeonucleotides as Novel Pharmacological Therapeutic Agents, Benjamin Weiss Basis to Toxicity Testing, Second Edition, Donald J. Ecobichon CNS Injuries: Cellular Responses and Pharmacological Strategies, Martin Berry and Ann Logan Lead and Public Health: Integrated Risk Assessment, Paul Mushak Molecular Bases of Anesthesia, Eric Moody and Phil Skolnick Receptor Characterization and Regulation, Devendrá K. Agrawal Published Titles Inflammatory Cells and Mediators in Bronchial Asthma, 1990, Devendrá K. Agrawal and Robert G. Townley Pharmacology of the Skin, 1991, Hasan Mukhtar In Vitro Methods of Toxicology, 1992, Ronald R. Watson Basis of Toxicity Testing, 1992, Donald J. Ecobichon Human Drug Metabolism from Molecular Biology to Man, 1992, Elizabeth Jeffreys Platelet Activating Factor Receptor: Signal Mechanisms and Molecular Biology, 1992, Shivendra D. Shukla Biopharmaceutics of Ocular Drug Delivery, 1992, Peter Edman Beneficial and Toxic Effects of Aspirin, 1993, Susan E. Feinman Preclinical and Clinical Modulation of Anticancer Drugs, 1993, Kenneth D. Tew, Peter Houghton, and Janet Houghton Peroxisome Proliferators: Unique Inducers of Drug-Metabolizing Enzymes, 1994, David E. Moody Angiotensin II Receptors, Volume I: Molecular Biology, Biochemistry, Pharmacology, and Clinical Perspectives, 1994, Robert R. Ruffolo, Jr. Angiotensin II Receptors, Volume II: Medicinal Chemistry, 1994, Robert R. Ruffolo, Jr. Pharmacology and Toxicology: Basic and Clinical Aspects Published Titles Continued Chemical and Structural Approaches to Rational Drug Design, 1994, David B. Weiner and William V. Williams Biological Approaches to Rational Drug Design, 1994, David B. Weiner and William V.Williams Direct Allosteric Control of Glutamate Receptors, 1994, M. Palfreyman, I. Reynolds, and P. Skolnick Genomic and Non-Genomic Effects of Aldosterone, 1994, Martin Wehling Human Growth Hormone Pharmacology: Basic and Clinical Aspects, 1995, Kathleen T. Shiverick and Arlan Rosenbloom Placental Toxicology, 1995, B. V. Rama Sastry Stealth Liposomes, 1995, Danilo Lasic and Frank Martin TAXOL®: Science and Applications, 1995, Matthew Suffness Endothelin Receptors: From the Gene to the Human, 1995, Robert R. Ruffolo, Jr. Alternative Methodologies for the Safety Evaluation of Chemicals in the Cosmetic Industry, 1995, Nicola Loprieno Phospholipase Ai in Clinical Inflammation: Molecular Approaches to Pathophysiology, 1995, Keith B. Glaser and Peter Vadas Serotonin and Gastrointestinal Function, 1995, Timothy S. Gaginella and James J. Galligan Drug Delivery Systems, 1996, Vasant V. Ranade and Mannfred A. Hollinger Experimental Models of Mucosal Inflammation, 1996, Timothy S. Gaginella Brain Mechanisms and Psychotropic Drugs, 1996, Andrius Baskys and Gary Remington Receptor Dynamics in Neural Development, 1996, Christopher A. Shaw Ryanodine Receptors, 1996, Vincenzo Sorrentino Therapeutic Modulation of Cytokines, 1996, M.W. Bodmer and Brian Henderson Pharmacology in Exercise and Sport, 1996, Satu M. Somani Placental Pharmacology, 1996, B. V. Rama Sastry Pharmacological Effects ofEthanol on the Nervous System, 1996, Richard A. Deitrich Immunopharmaceuticals, 1996, Edward S. Kimball Chemoattractant Ligands and Their Receptors, 1996, Richard Horuk Pharmacological Regulation of Gene Expression in the CNS, 1996, Kalpana Merchant Antibody Therapeutics, 1997, William J. Harris and John R. Adair Muscarinic Receptor Subtypes in Smooth Muscle, 1997, Richard M. Eglen ANTIBODY THERAPEUTICS Edited by William J. Harris, Ph.D. University of Aberdeen Aberdeen, Scotland John R. Adair, Ph.D. Axis Genetics, Pie. Babraham, Cambridge, United Kingdom Boca Raton London New York CRC Press is an imprint of the Taylor & Francis Group, an informa business CRCPress Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 Reissued 2019 by CRC Press © 1997 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an lnforma business No claim to original U.S. Government works This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www. copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. A Library of Congress record exists under LC control number: Publisher's Note The publisher has gone to great lengths to ensure the quality of this reprint but points out that some imperfections in the original copies may be apparent. Disclaimer The publisher has made every effort to trace copyright holders and welcomes correspondence from those they have been unable to contact. ISBN 13: 978-0-367-20057-2 (hbk) ISBN 13: 978-0-429-26036-0 (ebk) Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com INTRODUCTION John R. Adair Immunotherapy is now into its second century of application. 1 From the early use of serum therapy in the last years of the 19th Century to today when large numbers of monoclonal antibodies 2 (MAbs) and polyclonal antibody cocktails are being tested for efficacy in a variety of medical conditions the concept of the "magic bullet" has never disappeared. Antibodies have much to offer as pharmaceuticals. Immunoglob- ulin is a safe, long-lasting, naturally occurring product, present in the blood at 10-15 mg/ml. A vast range of antibody specificities of high affinity can be generated. The affinity of an antibody for antigen, for example, a cell-surface receptor, can exceed the affinity of the natural ligand for that receptor, and so antibodies can be considered for a range of therapeutic opportunities, from simple blockade (which includes entry of pathogens into cells) to sophisticated modulation of intracel- lular signaling, cell stimulation, anergy, or killing. Today the ability to generate specific human or human-like binding sites from a number of starting positions is relatively straightforward (see, for example, References 3 and 4). These binding sites can be linked genetically or chemically to a wide variety of effector elements, in a range of size and avidity formats.5 The products can be produced in a range of expression systems, offering high productivity and accurate processing. This modular approach to design can overcome many of the traditionally posed problems for antibody products, for example, immunogenicity, lack of efficacy, and inappropriate pharmacokinetics. The development of these engineered products has taken place over the last 20 years, post Kohler and Milstein. 2 Production of MAbs from cell culture increased the specific activity of an antibody prepa- ration, offering a potential reduction in the amount of antibody to be delivered or delivery of an efficacious dose of antibody in a reasonable formulation, thus widening the scope for therapeutic applications. MAbs also removed the problem of transfer of unnecessary blood components in immune globulin preparations and of adventitious infectious organisms. A number of phases can be identified in this period. Between 1975-1980 murine MAbs were prepared against a range of clinically relevant antigens including tumor-associated antigens, infectious microorganisms, blood proteins, and cell-surface antigens. For exam- ple, the murine anti-human CD3 MAb OKT3 was developed in 1979 and subsequently licensed in 1986 as ORTHOCLONE OKT®3 for use as an immunosuppressant for treatment of transplant rejection.6 In parallel, attempts were made during this time to derive human MAbs, but without much success (reviewed in Reference 7). During the period between 1980-1985 recombinant DNA tech- niques and expression technologies were applied to the antibody field. The gene structures of immunoglobulins were revealed and methods for the manipulation of antibody sequences and their expression in heterologous systems were first developed. The first domain swapping experiments to produce chimeric mouse-human antibodies were described,89 the possibility of antibody humanization was proposed,10 and early experiments to generate transgenic mice expressing human antibody genes were done.11 The concept of catalytic MAbs was dis- cussed.12 Several important intellectual property claims were made during this period (summarized in Reference 13), some of which are still being argued over. Between 1986-1990 commercial antibody engineering began to be taken seriously and many important developments occurred. The range of possible antibody-based products widened with the genera- tion of recombinant antibody fragments,1416 antibody binding sites fused to other protein entities (reviewed in References 17-20), and non- antibody binding sites linked to antibody Fc regions (immunoadhesins and receptor globulins).2122 Bacterial expression systems became avail- able for the efficient production of these novel entities,1415 while mam- malian cell23 and yeast24 systems were developed for whole antibody production based on other examples from the biotechnology industry. These systems allowed production levels in excess of that produced by hybridomas in cell culture. During this period the first humanized antibodies were produced,25 and the first recombinant antibodies entered clinical studies.26-27 In the period from 1990 to the present, these achievements have been further developed with a wide range of engineered antibodies entering clinical studies. The rate of entry into clinical trials of these product candidates is accelerating; for example, the number of human- ized antibodies in the clinic has doubled in the last 12 months. 2829 One of these engineered antibodies has already emerged as a product. Fur- ther developments include: the addition of combinatorial library pro- cedures for the production of novel human antibodies;34 progress in in vitro immunization as a means of generating novel specificities (e.g., Reference 30); a clearer understanding of the measures needed to be taken to ensure efficient humanization of the vast range of nonhuman MAbs which now exist;31 and the use of antibodies as platforms for the presentation of antigenic peptides (reviewed in Reference 32). Explicit links to the pharmaceutical drug development process have been made using antibody33 or minibody34 library screening systems, and the use of anti-receptor antibodies to prepare secondary structure mimics of interesting ligands.35 In addition, large-scale production systems have now progressed to the point where economical production is feasible36-38 (see also Chapters 9 and 10) which should allow the use of human and humanized antibodies as chronic, as well as acute treat- ments. Novel expression systems have also emerged that may ulti- mately challenge the more traditional methods for cost-effective production3940 (see Chapter 11). This book developed from a wish to present a timely summary of the progress of antibody products through development and clinical studies into the market place. Therefore, a focus of the book is with these latter phases of engineered antibody development. This book is divided into a number of sections. In the first section the chapters describe recent developments in antibody R+D which will provide the platform for further product development. The focus is on how the antibody achieves a therapeutic effect post-binding. M. Clark (Cambridge) has reviewed recent progress in the use of unconjugated antibodies as therapeutics, including their use in antigen blockade, recruitment of antibody-dependent cellular cytotoxicity (ADCC) and complement, and situations where bispecific antibodies might be of benefit. Three chapters then describe the use of antibodies for delivery of toxins (R. Kreitman and I. Pastan, NIH), drugs and radioisotopes (G. Yarranton, Celltech), and enzymes for the activation of prodrugs (I. Benhar and I. Pastan, NIH). These chapters principally deal with the use of antibodies for treatment of cancers, which has been a major focus of antibody therapeutics development. Chapters in the next section identify alternative uses for antibody therapeutics. The second section provides an insight into areas where antibodies are being considered as products. Recent surveys of antibodies in development2941 suggest that while there is still a predominance in the use of antibodies as anti-cancer platforms, recombinant MAbs are being considered for use in a much broader range of indications. The use of antibodies for the treatment of cancer is not dealt with here as a separate subject as it has been reviewed extensively elsewhere and permeates many of the other individual chapters in Sections I and IV. W. Harris (Aberdeen) summarizes the use of immune globulins and MAbs in the treatment of infectious diseases. L. Chatenoud (Oxford) describes opportunities for the use of antibodies in autoimmune situations. ORTHOCLONE OKT®3 has been licensed for use in renal transplanta- tion for 10 years. M. Alegre (Belgium) provides an update on the

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