The Pharmacology of Monoclonal Antibodies
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1 The Pharmacology of Monoclonal Antibodies Contributors R. Balint, C.F. Barbas, R.D. Blumenthal, P. Carter, M. Chatterjee Chen, Y.-C. Jack, R.M. Conry, K.A. Foon, D.M. Goldenberg E. Haber, M. Hein, A. Hiatt, K. James, K.D. Janda, K. Karjalainen H. Kohler, J.W. Larrick, A.F. LoBuglio, N. Lonberg, G.E. Mark E.A. Padlan, S.H. Pincus, A. Pluckthun, M.L. Rodrigues R.G. Rupp, M.N. Saleh, M.R. Shalaby, R.M. Sharkey A. Traunecker Editors Martin Rosenberg and Gordon P. Moore Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona Budapest
2 Contents Section I: Human Monoclonal Antibodies CHAPTER 1 Human Monoclonal Antibody Technology K. JAMES. With 2 Figures 3 A. Introduction 3 I. Why Produce Human Monoclonals? 3 II. Chapter Aims 3 III. Approach Used 4 B. General Production Strategies 4 I. Introduction 4 II. Source of Immune Lymphocytes 4 1. Usual Sources 4 2. In Vitro Immunization 7 3. Generating Immune Lymphocytes in Severe Combined Immunodeficiency Mice 7 III. Processing of Lymphoid Tissues 8 IV. Immortalization Strategies 8 1. Introduction 8 2. Cell Fusion 9 3. Epstein-Barr Virus Fusion Combined Epstein-Barr Virus Transformation and Cell Fusion Novel Approaches 11 V. Selection, Cloning and Expansion Introduction Selection Cloning Expansion Additional Evaluation 12 VI. Bispecific and Trispecific Antibodies 13 C. Human Monoclonal Targets 13 I. Antibody Specificities Generated 13
3 XII Contents II. Application of Human Monoclonal Antibody Technology Introduction Tumour Field AIDS Research Autoimmunity Future Targets 16 D. Limitations of Orthodox Technology 16 I. Introduction 16 II. Why Is Antibody Secretion Unsatisfactory? 17 III. Is Unsatisfactory Secretion Related to Cell Surface Phenotype or Cytokine Secretion? 17 E. Conclusion 18 I. Impact and Potential of Recombinant Technology Chimeric and Humanized Antibodies Repertoire Cloning Combining Cell and Gene Cloning Technologies 19 References 19 CHAPTER 2 Recombinant Therapeutic Human Monoclonal Antibodies J.W. LARRICK and R. BALINT 23 A. Therapeutic Human Monoclonal Antibodies 23 B. Rapid Direct Cloning of Antibody Variable Regions 25 C. Genetically Engineered Chimeric Monoclonal Antibodies 30 I. Chimeric Antibodies Summary of Work with Therapeutic Chimeric Monoclonal Antibodies 31 II. Recombinant Conjugates and Fusion Proteins Immunotoxins A Recombinant Monoclonal Antibody Linked to Tissue-Type Plasminogen Activator T Cell Receptor Conjugates Growth Factor Conjugates Other Fusion Proteins Antibody-Enzyme Conjugates for Cancer 34 D. Reshaped or Composite Antibodies 35 E. Immortalization of the Immunoglobulin Repertoire Using rdna Technology 37 F. Recombinatorial Antibody Libraries 38 G. Phage Antibody Libraries: Wholly Synthetic Monoclonal Antibodies 39 References 41
4 Contents XIII CHAPTER 3 Transgenic Approaches to Human Monoclonal Antibodies N. LONBERG. With 11 Figures 49 A. Introduction 49 B. Competing Technologies for the Generation of Therapeutic Antibodies 50 C. Origins of Antibody Diversity 52 I. Functional Requirements for a Human Immunoglobulin Transgene 52 II. Structure of the Human Immunoglobulin Loci The Human X Light Chain Locus The Human K Light Chain Locus The Human Heavy Chain Locus 57 D. Transgenic Technology 58 I. Pronuclear Microinjection 59 II. Embryonic Stem Cells 59 III. Transgene Constructs Bacteriophage Cloning Vectors Plasmid Cloning Vectors Yeast Artificial Chromosome Vectors 62 E. Immunoglobulin Transgenics. 64 I. High Level and Cell Type Specific Expression Cw-acting Regulatory Sequences Transgene Expression Human Transgene Constructs 65 II. Rearrangement Target Sequences Immunoglobulin Gene Rearrangements in Transgenic Mice Light Chain Junctions Heavy Chain Junctions Repercussions of Mouse B Cell Environment on Human VDJ Joints 71 III. Allelic Exclusion Background Induction of Allelic Exclusion by Rearranged Transgenes Response to Allelic Exclusion by Unrearranged Transgenes Alternatives to Direct Feedback Allelic Exclusion 77 IV. Primary Repertoire 77 V. Intracellular Signaling Background B Cell Receptor Complex 79
5 XIV Contents 3. Pre-B Cell Complex 81 VI. Class Switching Background Class Switching in Transgenic Mice Importance of Class Switching for a Human Antibody Mouse 83 VII. Substrate for Somatic Mutation 85 VIII. Domination of the Immune Response Antibody Depletion Anti-sense Transgenes Gene Targeting 88 F. Perspective 89 References 90 Section II: Genetically Engineered Monoclonal Antibodies CHAPTER 4 Humanization of Monoclonal Antibodies G.E. MARK and E.A. PADLAN. With 10 Figures 105 A. Introduction 105 B. Structure of Antibodies 105 I. General 105 II. The Antibody Combining Site 107 III. Complementarity Determining Regions 107 IV. Influence of Framework Residues on Combining Site Structure 108 C. Strategies for the Humanization of Antibodies 109 I. Transplanting a Nonhuman Combining Site onto a Human Framework 109 II. Recombinant Methodology of Complementarity Determining Region Transfer Polymerase Chain Reaction-Mediated Complementarity Determining Region Transfer Humanization of the Murine Monoclonal Antibody IB Antibody Reshaping 122 III. Replacing Surface Residues to Humanize (Veneering) D. Immunogenicity of Humanized Antibodies 130 E. Conclusion 131 References 132
6 Contents XV CHAPTER 5 Applications for Escherichia co//-derived Humanized Fab' Fragments: Efficient Construction of Bispecific Antibodies P. CARTER, M.L. RODRIGUES, and M.R. SHALABY. With 3 Figures 135 A. Introduction 135 B. Choice of Antigen Specificities for Bispecific F(ab') C. Expression of Humanized Fab' Fragments in E. coli 137 D. Recovery of Fab'-SH Fragments 138 E. Construction of Bispecific F(ab') F. Uses of E. coli-derived Fab' Fragments 141 G. Conclusions 143 References 143 Section III: MAb Conjugates and Fusions CHAPTER 6 Immunotoxins S.H. PINCUS. With 2 Figures 149 A. Introduction 149 B. Considerations in Immunotoxin Development 150 I. In Vitro Testing To Identify Effective Antibodies 150 II. Immunotoxin Design 151 C. The Toxic Moiety 153 I. Ricin 154 II. Pseudomonas Exotoxin A 154 III. Diphtheria Toxin 157 IV. Drug Conjugates 157 V. Novel Approaches 158 D. Cell Biology of Immunotoxin Action 159 E. Pharmacology of Immunotoxin Administration 160 I. Pharmacokinetics 160 II. Pharmacologic Enhancement of Immunotoxin Action 161 III. Immunogenicity 162 F. Clinical Applications 163 I. Cancer 163 II. Immunosuppression Transplantation Autoimmune Disease 166 III. Infectious Diseases 167
7 XVI Contents IV. Disordered Cellular Growth 168 G. Conclusions 168 References 170 CHAPTER 7 Antibody-Enzyme Fusion Proteins and Bispecific Antibodies E. HABER. With 2 Figures 179 A. Introduction 179 B. Antibody-Enzyme Fusion Proteins 179 I. Development of the Concept of a Bifunctional Protein II. Chemically Cross-Linked Conjugates as Models for Fusion Proteins Cross-Linked Antibody-Plasminogen Activator Conjugates Methods for Synthesizing and Purifying Cross-Linked Conjugates 182 III. Fusion Protein Construction Cloning the Rearranged Immunoglobulin Gene Constructing the Expression Vector Selecting Loss Variant Cell Lines Transfecting the Expression Plasmid Purifying and Analyzing Protein Recombinant Protein Expression Levels 185 IV. Structural and Functional Properties of Specific Fusion Proteins Antibody-Plasminogen Activator Fusion Proteins A Model Minimal Size Fusion Protein Fv and Single Chain Fv Minimal Fv-Containing Fusion Protein Prodrug Activation 190 C. Bispecific Antibodies 192 I. Development of the Concept of a Bispecific Antibody 192 II. Chemically Cross-Linked Bispecific Antibodies as Models 192 III. Cell Fusion in the Production of Bispecific Antibodies 192 IV. Functional Properties of Bispecific Antibodies 193 D. Conclusion 193 References 194
8 Contents XVII CHAPTER 8 Three Generations of Recombinant CD4 Molecules as Anti-HIV Reagents A. TRAUNECKER and K. KARJALAINEN. With 2 Figures 199 A. Introduction 199 B. General Aspects of HIV Infection 199 C. Characteristics of Different Forms of scd4 200 I. First Generation: Truncated Forms of scd4 200 II. Second Generation: CD4-Immunoglobulins 200 III. Third Generation: CD4-FvCD3 Janusins 201 D. Molecular Designs and Strategies to Produce Recombinant CD4 Molecules 202 I. Production of scd4 Molecules 202 II. CD4-CK Molecules 202 III. Multivalent scd4 Molecules: CD4 Immunoglobulins 203 IV. Bispecific Reagents: CD4-FvCD3 Janusins 204 E. Concluding Remarks 205 References 205 Section IV: Combinatorial Libraries CHAPTER 9 Chemical and Biological Approaches to Catalytic Antibodies K.D. JANDA and Y.-C. JACK CHEN. With 18 Figures 209 A. Introduction 209 B. Background 211 I. Bases of Enzymatic Catalysis 211 C. Hapten Design Strategies for Catalytic Antibodies 215 I. Transition State Stabilization 215 II. Entropic Effects 222 III. Charge Complementarity 223 IV. Solvent Effects 225 D. Catalytic Antibodies in Organic Solvents 227 E. Biological Aspects 229 I. Hybridoma Techniques 229 II. Auxotrophic Selection 230 III. Expression Methods 233 F. Prospects 236 References 237
9 XVIII Contents CHAPTER 10 The Combinatorial Approach to Human Antibodies C.F. BARBAS III. With 10 Figures 243 A. Introduction 243 B. The Combinatorial Approach 243 C. From Screening to Selection 245 D. Features of the Combinatorial Approach 248 E. Human Antiviral Antibodies 251 I. Introduction 251 II. Antibodies to HIV Rationale Source of RNA Characterization of Antibodies 253 III. Antibodies to Respiratory Syncytial Virus 256 IV. Antibodies to Hepatitis B Virus 258 F. Alternatives to the Use of Seropositive Humans 258 I. Naive Libraries 258 II. Synthetic and Semisynthetic Antibodies 260 III. Human Antibodies from Severe Combined Immunodeficiency Mice 260 IV. Antibodies from Chimpanzees 261 G. Production of Whole Antibodies and Gene Rescue from Cell Lines 261 H. The Future of Antibodies 262 References 263 Section V: Expression of MAbs/MAb Fragments CHAPTER 11 Antibodies from Escherichia coli A. PLUCKTHUN. With 11 Figures 269 A. Introduction 269 B. Expression of Functional Antibody Fragments in E. coli by Secretion 270 I. General Overview 270 II. Relation of Functional Secretion to Phage Libraries 272 III. Description of the Secretion Process 274 IV. The Role of Periplasmic Protein Folding 276 V. Catalysis of Periplasmic Protein Folding Disulfide Bond Formation Proline cis-trans Isomerization 280
10 Contents XIX VI. Design of Secretion Vectors 281 VII. Fermentation 286 VIII. Cloning Antibodies by Polymerase Chain Reaction 287 IX. Purification 288 C. Expression of Antibody Fragments as Inclusion Bodies 289 D. Antibody Fragments 292 I. Fv Fragments 293 II. Single Chain Fv Fragments 294 III. Disulfide-Linked Fv Fragments 296 IV. Mini-antibodies Mini-antibodies Based on Coiled-Coil Helices Mini-antibodies Based on Four-Helix Bundles 303 E. Conclusions 304 References 304 CHAPTER 12 Structure, Function and Uses of Antibodies from Transgenic Plants and Animals A. HIATT and M. HEIN 317 A. Introduction 317 B. Transgenic Antibodies from Mice 318 C. Potential Uses of Antibody Expression in Transgenic Animals I. Investigation of Immune System Regulation 318 II. Human Monoclonal Antibodies in Animals 319 III. Pathogen Protection in Agricultural Animals 319 D. Transgenic Antibodies from Plants 320 E. Structure and Function of Antibodies from Plants 322 I. Glycosylation of Antibodies Produced in Plants 323 II. Antibody Processing and Assembly 323 III. Mutagenesis to Remove N-Linked Glycosylation 324 IV. Deletion of Heavy Chain Constant Regions 325 F. Potential Uses of Antibodies Expressed in Transgenic Plants I. Scale and Economics of Plantibody Production 325 II. Potential Medical Uses of Plant Produced Antibodies 326 III. Pathogen Protection in Agricultural Plants 327 References 328 CHAPTER 13 Some Aspects of Monoclonal Antibody Production R.G. RUPP. With 4 Figures 331 References 344
11 XX Contents Section VI: Medical Applications CHAPTER 14 Prospects for Cancer Imaging and Therapy with Radioimmunoconjugates D.M. GOLDENBERG, R.D. BLUMENTHAL, and R.M. SHARKEY. With 2 Figures : 347 A. Introduction 347 B. Nature and Pharmacology of Radioimmunoconjugates 347 C. Radioimmunoconjugates in Detection vs Therapy 350 D. Nature and Problems of Radioimmunodetection 351 E. Nature and Problems of Radioimmunotherapy 353 F. Current Clinical Status of Radioimmunotherapy 357 G. Experimental Studies of Adjuvant Radioimmunotherapy 359 H. Conclusions and Future Prospects 362 References 362 CHAPTER 15 Clinical Experience with Murine, Human and Genetically Engineered Monoclonal Antibodies M.N. SALEH, R.M. CONRY, and F. LOBUGLIO 369 A. Introduction 369 B. Difficulties Encountered with Murine Monoclonal Reagents 370 I. Immunogenicity of Murine Antibodies 370 II. Pharmacokinetics of Murine Antibodies 371 III. Clinical Efficacy of Murine Antibodies In Cancer In Nonmalignant Disorders 373 IV. Toxicity Associated with Murine Antibodies 374 C. Human Monoclonal Antibody Trials 374 D. Chimeric Antibody Trials 376 E. CDR-Grafted Humanized Monoclonal Antibody Trials 378 F. Future Prospects 379 References 380
12 Contents XXI CHAPTER 16 Anti-idiotypic Monoclonal Antibodies: Novel Approach to Immunotherapy M. CHATTERJEE, K.A. FOON, and H. KOHLER. With 1 Figure 387 A. Introduction 387 B. Advantages of Anti-idiotypic Antibodies Over Conventional Vaccines 388 C. Acquired Immune Deficiency Syndrome 389 D. Solid Tumors and Cutaneous T Cell Lymphoma 391 E. B Cell Lymphomas and Leukemias 394 F. Conclusion 396 References 397 Subject Index 403
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