The pharmacology of monoclonal antibodies (handbook of experimental pharmacology), Softcover reprint of the original 1st ed. 1994
Handbook of Experimental Pharmacology Series, Vol. 113

Coordinators: Rosenberg Martin, Moore Gordon P.

Language: Anglais

137.14 €

In Print (Delivery period: 15 days).

Add to cartAdd to cart
Publication date:
406 p. · 15.5x23.5 cm · Paperback
This volume surveys recent developments in the cloning, manipulation, expression and application of genetically-engineered monoclonal antibodies. Leading researchers present their own findings and review related areas.
Section I: Human Monoclonal Antibodies.- 1 Human Monoclonal Antibody Technology.- A. Introduction.- I. Why Produce Human Monoclonals?.- II. Chapter Aims.- III. Approach Used.- B. General Production Strategies.- I. Introduction.- II. Source of Immune Lymphocytes.- 1. Usual Sources.- 2. In Vitro Immunization.- 3. Generating Immune Lymphocytes in Severe Combined Immunodeficiency Mice.- III. Processing of Lymphoid Tissues.- IV. Immortalization Strategies.- 1. Introduction.- 2. Cell Fusion.- 3. Epstein-Barr Virus Fusion.- 4. Combined Epstein-Barr Virus Transformation and Cell Fusion.- 5. Novel Approaches.- V. Selection, Cloning and Expansion.- 1. Introduction.- 2. Selection.- 3. Cloning.- 4. Expansion.- 5. Additional Evaluation.- VI. Bispecific and Trispecific Antibodies.- C. Human Monoclonal Targets.- I. Antibody Specificities Generated.- II. Application of Human Monoclonal Antibody Technology.- 1. Introduction.- 2. Tumour Field.- 3. AIDS Research.- 4. Autoimmunity.- 5. Future Targets.- D. Limitations of Orthodox Technology.- I. Introduction.- II. Why Is Antibody Secretion Unsatisfactory?.- III. Is Unsatisfactory Secretion Related to Cell Surface Phenotype or Cytokine Secretion?.- E. Conclusion.- I. Impact and Potential of Recombinant Technology.- 1. Chimeric and Humanized Antibodies.- 2. Repertoire Cloning.- 3. Combining Cell and Gene Cloning Technologies.- References.- 2 Recombinant Therapeutic Human Monoclonal Antibodies.- A. Therapeutic Human Monoclonal Antibodies.- B. Rapid Direct Cloning of Antibody Variable Regions.- C. Genetically Engineered Chimeric Monoclonal Antibodies.- I. Chimeric Antibodies.- 1. Summary of Work with Therapeutic Chimeric Monoclonal Antibodies.- II. Recombinant Conjugates and Fusion Proteins.- 1. Immunotoxins.- 2. A Recombinant Monoclonal Antibody Linked to Tissue-Type Plasminogen Activator.- 3. T Cell Receptor Conjugates.- 4. Growth Factor Conjugates.- 5. Other Fusion Proteins.- 6. Antibody-Enzyme Conjugates for Cancer.- D. Reshaped or Composite Antibodies.- E. Immortalization of the Immunoglobulin Repertoire Using rDNA Technology.- F. Recombinatorial Antibody Libraries.- G. Phage Antibody Libraries: Wholly Synthetic Monoclonal Antibodies.- References.- 3 Transgenic Approaches to Human Monoclonal Antibodies.- A. Introduction.- B. Competing Technologies for the Generation of Therapeutic Antibodies.- C. Origins of Antibody Diversity.- I. Functional Requirements for a Human Immunoglobulin Transgene.- II. Structure of the Human Immunoglobulin Loci.- 1. The Human ? Light Chain Locus.- 2. The Human ? Light Chain Locus.- 3. The Human Heavy Chain Locus.- D. Transgenic Technology.- I. Pronuclear Microinjection.- II. Embryonic Stem Cells.- III. Transgene Constructs.- 1. Bacteriophage Cloning Vectors.- 2. Plasmid Cloning Vectors.- 3. Yeast Artificial Chromosome Vectors.- E. Immunoglobulin Transgenics.- I. High Level and Cell Type Specific Expression.- 1. Cis-acting Regulatory Sequences.- 2. Transgene Expression.- 3. Human Transgene Constructs.- II. Rearrangement.- 1. Target Sequences.- 2. Immunoglobulin Gene Rearrangements in Transgenic Mice.- 3. Light Chain Junctions.- 4. Heavy Chain Junctions.- 5. Repercussions of Mouse B Cell Environment on Human VDJ Joints.- III. Allelic Exclusion.- 1. Background.- 2. Induction of Allelic Exclusion by Rearranged Transgenes.- 3. Response to Allelic Exclusion by Unrearranged Transgenes.- 4. Alternatives to Direct Feedback Allelic Exclusion.- IV. Primary Repertoire.- V. Intracellular Signaling.- 1. Background.- 2. B Cell Receptor Complex.- 1. Pre-B Cell Complex.- II. Class Switching.- 1. Background.- 2. Class Switching in Transgenic Mice.- 3. Importance of Class Switching for a Human Antibody Mouse.- III. Substrate for Somatic Mutation.- IV. Domination of the Immune Response.- 1. Antibody Depletion.- 2. Anti-sense Transgenes.- 3. Gene Targeting.- A. Perspective.- References.- Section II: Genetically Engineered Monoclonal Antibodies.- 4 Humanization of Monoclonal Antibodies.- A. Introduction.- B. Structure of Antibodies.- I. General.- II. The Antibody Combining Site.- III. Complementarity Determining Regions.- IV. Influence of Framework Residues on Combining Site Structure.- C. Strategies for the Humanization of Antibodies.- I. Transplanting a Nonhuman Combining Site onto a Human Framework.- II. Recombinant Methodology of Complementarity Determining Region Transfer.- 1. Polymerase Chain Reaction-Mediated Complementarity Determining Region Transfer.- 2. Humanization of the Murine Monoclonal Antibody IB4.- 3. Antibody Reshaping.- III. Replacing Surface Residues to Humanize (Veneering).- D. Immunogenicity of Humanized Antibodies.- E. Conclusion.- References.- 5 Applications for Escherichia coli-Derived Humanized Fab’ Fragments: Efficient Construction of Bispecific Antibodies.- A. Introduction.- B. Choice of Antigen Specificities for Bispecific F(ab’)2.- C. Expression of Humanized Fab’ Fragments in E. coli.- D. Recovery of Fab’-SH Fragments.- E. Construction of Bispecific F(ab’)2.- F. Uses of E. coli-Derived Fab’ Fragments.- G. Conclusions.- References.- Section III: MAb Conjugates and Fusions.- 6 Immunotoxins.- A. Introduction.- B. Considerations in Immunotoxin Development.- I. In Vitro Testing To Identify Effective Antibodies.- II. Immunotoxin Design.- C. The Toxic Moiety.- I. Ricin.- II. Pseudomonas Exotoxin A.- III. Diphtheria Toxin.- IV. Drug Conjugates.- V. Novel Approaches.- D. Cell Biology of Immunotoxin Action.- E. Pharmacology of Immunotoxin Administration.- I. Pharmacokinetics.- II. Pharmacologic Enhancement of Immunotoxin Action.- III. Immunogenicity.- F. Clinical Applications.- I. Cancer.- II. Immunosuppression.- 1. Transplantation.- 2. Autoimmune Disease.- III. Infectious Diseases.- I. Disordered Cellular Growth.- A. Conclusions.- References.- 7 Antibody-Enzyme Fusion Proteins and Bispecific Antibodies.- A. Introduction.- B. Antibody-Enzyme Fusion Proteins.- I. Development of the Concept of a Bifunctional Protein.- II. Chemically Cross-Linked Conjugates as Models for Fusion Proteins.- 1. Cross-Linked Antibody-Plasminogen Activator Conjugates.- 2. Methods for Synthesizing and Purifying Cross-Linked Conjugates.- III. Fusion Protein Construction.- 1. Cloning the Rearranged Immunoglobulin Gene.- 2. Constructing the Expression Vector.- 3. Selecting Loss Variant Cell Lines.- 4. Transfecting the Expression Plasmid.- 5. Purifying and Analyzing Protein.- 6. Recombinant Protein Expression Levels.- IV. Structural and Functional Properties of Specific Fusion Proteins.- 1. Antibody-Plasminogen Activator Fusion Proteins.- 2. A Model Minimal Size Fusion Protein.- 3. Fv and Single Chain Fv.- 4. Minimal Fv-Containing Fusion Protein.- 5. Prodrug Activation.- C. Bispecific Antibodies.- I. Development of the Concept of a Bispecific Antibody.- II. Chemically Cross-Linked Bispecific Antibodies as Models.- III. Cell Fusion in the Production of Bispecific Antibodies.- IV. Functional Properties of Bispecific Antibodies.- D. Conclusion.- References.- 8 Three Generations of Recombinant CD4 Molecules as Anti-HIV Reagents.- A. Introduction.- B. General Aspects of HIV Infection.- C. Characteristics of Different Forms of sCD4.- I. First Generation: Truncated Forms of sCD4.- II. Second Generation: CD4-Immunoglobulins.- III. Third Generation: CD4-FvCD3 Janusins.- D. Molecular Designs and Strategies to Produce Recombinant CD4 Molecules.- I. Production of sCD4 Molecules.- II. CD4-Ck Molecules.- III. Multivalent sCD4 Molecules: CD4 Immunoglobulins.- IV. Bispecific Reagents: CD4-FvCD3 Janusins.- E. Concluding Remarks.- References.- Section IV: Combinatorial Libraries.- 9 Chemical and Biological Approaches to Catalytic Antibodies.- A. Introduction.- B. Background.- I. Bases of Enzymatic Catalysis.- C. Hapten Design Strategies for Catalytic Antibodies.- I. Transition State Stabilization.- II. Entropic Effects.- III. Charge Complementarity.- IV. Solvent Effects.- D. Catalytic Antibodies in Organic Solvents.- E. Biological Aspects.- I. Hybridoma Techniques.- II. Auxotrophic Selection.- III. Expression Methods.- F. Prospects.- References.- 10 The Combinatorial Approach to Human Antibodies.- A. Introduction.- B. The Combinatorial Approach.- C. From Screening to Selection.- D. Features of the Combinatorial Approach.- E. Human Antiviral Antibodies.- I. Introduction.- II. Antibodies to HIV-1.- 1. Rationale.- 2. Source of RNA.- 3. Characterization of Antibodies.- III. Antibodies to Respiratory Syncytial Virus.- IV. Antibodies to Hepatitis B Virus.- F. Alternatives to the Use of Seropositive Humans.- I. Naive Libraries.- II. Synthetic and Semisynthetic Antibodies.- III. Human Antibodies from Severe Combined Immunodeficiency Mice.- IV. Antibodies from Chimpanzees.- G. Production of Whole Antibodies and Gene Rescue from Cell Lines.- H. The Future of Antibodies.- References.- Section V: Expression of MAbs/MAb Fragments.- 11 Antibodies from Escherichia coli.- A. Introduction.- B. Expression of Functional Antibody Fragments in E. coli by Secretion.- I. General Overview.- II. Relation of Functional Secretion to Phage Libraries.- III. Description of the Secretion Process.- IV. The Role of Periplasmic Protein Folding.- V. Catalysis of Periplasmic Protein Folding.- 1. Disulfide Bond Formation.- 2. Proline cis-trans Isomerization.- II. Design of Secretion Vectors.- III. Fermentation.- IV. Cloning Antibodies by Polymerase Chain Reaction.- V. Purification.- A. Expression of Antibody Fragments as Inclusion Bodies.- B. Antibody Fragments.- I. Fv Fragments.- II. Single Chain Fv Fragments.- III. Disulfide-Linked Fv Fragments.- IV. Mini-antibodies.- 1. Mini-antibodies Based on Coiled-Coil Helices.- 2. Mini-antibodies Based on Four-Helix Bundles.- C. Conclusions.- References.- 12 Structure, Function and Uses of Antibodies from Transgenic Plants and Animals.- A. Introduction.- B. Transgenic Antibodies from Mice.- C. Potential Uses of Antibody Expression in Transgenic Animals.- I. Investigation of Immune System Regulation.- II. Human Monoclonal Antibodies in Animals.- III. Pathogen Protection in Agricultural Animals.- D. Transgenic Antibodies from Plants.- E. Structure and Function of Antibodies from Plants.- I. Glycosylation of Antibodies Produced in Plants.- II. Antibody Processing and Assembly.- III. Mutagenesis to Remove N-Linked Glycosylation.- IV. Deletion of Heavy Chain Constant Regions.- F. Potential Uses of Antibodies Expressed in Transgenic Plants.- I. Scale and Economics of Plantibody Production.- II. Potential Medical Uses of Plant Produced Antibodies.- III. Pathogen Protection in Agricultural Plants.- References.- 13 Some Aspects of Monoclonal Antibody Production.- References.- Section VI: Medical Applications.- 14 Prospects for Cancer Imaging and Therapy with Radioimmunoconjugates.- A. Introduction.- B. Nature and Pharmacology of Radioimmunoconjugates.- C. Radioimmunoconjugates in Detection vs Therapy.- D. Nature and Problems of Radioimmunodetection.- E. Nature and Problems of Radioimmunotherapy.- F. Current Clinical Status of Radioimmunotherapy.- G. Experimental Studies of Adjuvant Radioimmunotherapy.- H. Conclusions and Future Prospects.- References.- 15 Clinical Experience with Murine, Human and Genetically Engineered Monoclonal Antibodies.- A. Introduction.- B. Difficulties Encountered with Murine Monoclonal Reagents.- I. Immunogenicity of Murine Antibodies.- II. Pharmacokinetics of Murine Antibodies.- III. Clinical Efficacy of Murine Antibodies.- 1. In Cancer.- 2. In Nonmalignant Disorders.- IV. Toxicity Associated with Murine Antibodies.- C. Human Monoclonal Antibody Trials.- D. Chimeric Antibody Trials.- E. CDR-Grafted Humanized Monoclonal Antibody Trials.- F. Future Prospects.- References.- 16 Anti-idiotypic Monoclonal Antibodies: Novel Approach to Immunotherapy.- A. Introduction.- B. Advantages of Anti-idiotypic Antibodies Over Conventional Vaccines.- C. Acquired Immune Deficiency Syndrome.- D. Solid Tumors and Cutaneous T Cell Lymphoma.- E. B Cell Lymphomas and Leukemias.- F. Conclusion.- References.