Novel Therapeutics from Modern Biotechnology: From Laboratory to Human Testing

ISBN-13: 9783540650256 / Angielski / Twarda / 1998 / 248 str.

A. Abuchowski; Leonard E. Post; Dale L. Oxender

Opis

A cover story of Business Week Magazine in January 1984 stated "Biotech Comes of Age." In February 1986, Venture Magazine had a cover article entitled "The Biotech Revolution is Here." This article went on to say "New Genetic Technologies Will Transform Our Lives." These announcements were made many years after the first biotechnology companies, such as Genentech, Cetus, Amgen and Biogen, were formed-to commercialize the "New Biology." . At the time of writing this book, there are over 1300 biotech companies developing new technologies or identifying potential biotech drugs. Most of these companies were started in the height of the "high-technology hype," although companies are still forming as the technology advances. A more recent survey showed only a relatively small number of Food and Drug Administration (FDA) approvals among over several hundred biotech- nology products now in clinical trial. One could ask why it has taken so long to produce biotechnology products. Part of the reason is that each new class of biotech products brings with it a set of problems that need to be solved before they enter clinical trials. These problems are often unique to biotechnology products, such as peptides, proteins, monoclonal antibodies, nucleic acids and cellular therapies.

Spis treści

1 Overview of Regulatory Expectations for Introducing Novel Therapies into Clinical Trials.- A. Introduction.- B. Roles of Regulatory Scientists.- C. Product Development and Availability.- D. Data Requirements.- E. Manufacturing.- F. Preclinical Safety Testing.- G. Case-By-Case Approach.- H. Testing Goals.- I. Study Design.- J. Defining Exposure.- K. Product-Specific Concerns.- L. Accessibility of Preclinical Safety Data.- M. Clinical Studies.- I. Early Development.- II. Late Development.- N. Summary.- References.- 2 Preparation of Clinical Trial Supplies of Biopharmaceuticals.- A. Introduction.- I. Research Support Systems.- B. Preclinical Studies.- C. Clinical Supplies.- I. Fermentation.- II. Harvest.- III. Purification.- D. Purification of rDNA-Derived Anti-RSV MAb.- E. Product Quality Issues.- I. Protein Purity.- II. Protein Integrity.- III. Microbial and Viral Safety.- IV. Other Contaminants.- F. Process Design and Validation.- I. Validation of Endotoxin Removal.- II. Process Validation of Model Virus Clearance.- G. Process Economics and the Future of Chromatography.- I. Process Automation and Control.- II. Generic Purification Methods.- H. Conclusions.- References.- 3 Proteins as Drugs: Analysis, Formulation and Delivery.- A. Introduction.- B. The Analysis of Protein Pharmaceuticals.- I. X-Ray Crystallography.- II. Nuclear Magnetic Resonance.- III. Mass Spectroscopy.- IV. Multiple Parametric Approaches.- V. Miscellaneous Comments.- C. Formulation.- D. Delivery.- I. Controlled-Release Dosage Forms.- II. A Practical Delivery Challenge: Insulin.- References.- 4 Strategies for Dealing With the Immunogenicity of Therapeutic Proteins.- A. Introduction.- B. Case Histories of Protein Therapeutic Development.- I. Insulin.- II. Growth Hormone.- III. Asparaginase.- IV. Glucocerebrosidase.- V. OKT3.- C. Strategies Under Development for Increasing the Therapeutic Value of Proteins and Peptides.- I. Encapsulation.- II. Non-Parenteral Routes of Administration.- III. Targeting.- IV. Conjugation.- V. Protein Engineering.- D. Choosing the Proper Strategy for a Protein Therapeutic.- E. The Future of Protein Therapeutics.- References.- 5 Targeted Toxin Hybrid Proteins.- A. Introduction.- I. Protein Toxins That Inhibit Protein Synthesis.- 1. Plant Toxins.- 2. Bacterial Toxins.- II. Structure and Function of Pseudomonas Exotoxin.- 1. Definition of Domains and Mechanism of Intoxication.- 2. Mutants Lacking Cell Binding.- III. Types of Toxins Made with PE.- 1. Chemical Conjugates vs Recombinant Fusions.- 2. Fusion Toxins Containing Transforming Growth Factor-?.- 3. Fusion Toxins Containing Interleukin 2.- 4. Recombinant Immunotoxins.- B. Preclinical Development of Anti-Tac(Fv) Toxins.- I. Background.- II. Efficacy Data on Relevant Human Cells.- 1. Human Activated T-Lymphocytes.- 2. Fresh Adult T-Cell Leukemia Cells.- 3. Fresh Chronic Lymphocytic Leukemia Cells.- III. Efficacy Data in an Animal Model of IL2R-Bearing Cancer.- 1. Production of the Human ATAC-4 Line.- 2. Toxicity of Anti-Tac(Fv) Toxins in Mice.- 3. Pharmacokinetics in Mice.- 4. Antitumor Activity in Tumor-Bearing Mice.- IV. Primate Testing.- 1. Pharmacokinetics in Cynomolgus Monkeys.- 2. Toxicity in Cynomolgus Monkeys.- V. Production Issues.- C. Preclinical Development of Inerleukin 6-PE4E.- I. Background.- II. Study of IL6-PE4E For Ex Vivo Marrow Purging in Multiple Myeloma.- 1. Rationale.- 2. Efficacy Against Fresh Marrow Cells from Myeloma Patients.- 3. Safety Toward Fresh Normal Marrow Cells.- 4. Safety of IL6-PE4EToward Normal Hematopoietic Progenitors.- 5. Lack of Prevention of Bone Marrow Engraftment.- 6. Carryover of IL6-PE4E In Vivo.- III. Production of IL6-PE4E.- D. Summary.- References.- 6 SB 209763: A Humanized Monoclonal Antibody for the Prophylaxis and Treatment of Respiratory Syncytial Virus Infection.- A. Introduction.- B. Early Challenges in the Development of SB 209763.- I. Selection of Target Antigen.- II. Molecular Engineering of SB 209763.- III. Production.- IV. Primary Structure Analysis.- C. Preclinical Evaluation Prior to Testing in Humans.- I. Fusion Inhibition: An In Vitro Correlate of Protection.- II. Antigenic Variation.- III. Animal Models of Respiratory Syncytial Virus Infection.- IV. Safety and Pharmacokinetics.- D. Challenges for the Early Clinical Development of SB 209763.- I. Selection of the Initial Study Population and Safety Considerations.- II. Pharmacodynamic Markers to Establish Pharmacologic Effect.- III. Formulation Considerations for Clinical Studies.- IV. Surveillance for Anti-SB 209763 Antibodies.- V. Transition to the Target Pediatric Population and Choice of Dose.- VI. Results of Early Clinical Studies.- E. Conclusion.- References.- 7 Preclinical Development of Antisense Therapeutics.- A. Introduction.- B. Pharmacology of Antisense Oligodeoxynucleotides.- I. Molecular Pharmacology of Antisense Oligodeoxynucleotides.- II. In Vivo Pharmacology of Antisense Oligodeoxynucleotides.- C. Pharmacokinetics and Toxicity of Oligodeoxynucleotide Therapeutics.- I. Pharmacokinetics and Metabolism.- II. Toxicity of Phosphorothioate Oligodeoxynucleotides.- D. Chemistry, Manufacture and Control of Phosphorothioate Oligodeoxynucleotide Drugs.- I. Synthesis of Phosphorothioate Oligodeoxynucleotides.- 1. Chemistry of Elongation.- 2. Chemistry of Sulfurization.- 3. O,O-Linked Phosphorothioate DNA Diastereoisomerism.- II. Purification of Phosphorothioate Oligodeoxynucleotides.- III. Quality Control of Phosphorothioate Oligodeoxynucleotides.- E. Formulation and Drug Delivery of Oligodeoxynucleotides.- I. Physical—Chemical Properties.- II. Formulation.- III. Drug Delivery: Targeting, Uptake and Release.- F. Summary.- References.- 8 Formulation and Delivery of Nucleic Acids.- A. Introduction.- B. Formulation of DNA.- I. Naked-DNA Injections.- II. Gene Guns.- III. Polymer-Based Formulations.- IV. Lipid-Based Formulations.- 1. Liposome Encapsulation.- 2. Cationic Lipid/Nucleotide Complex.- 3. DNA-Binding Moiety.- 4. Hydrophobic Moiety.- 5. Spacer.- 6. Linker.- 7. Helper Lipid.- C. Delivery to Target Cells.- D. Cell Entry.- I. Receptor-Mediated Uptake.- E. Endosomal Release.- F. Nuclear Localization.- G. Gene Expression.- References.- 9 Safe, Efficient Production of Retroviral Vectors.- A. Introduction.- B. Vectors.- I. Retroviral Vectors.- C. Production of Retroviral Vectors.- I. Production Methods.- 1. Batch Systems.- 2. Roller Bottles.- 3. Multilayered Propagator.- II. Bioreactors.- 1. CellCube Bioreactor.- 2. Hollow-Fiber Bioreactor.- 3. Microcarrier Beads in Bioreactor.- 4. Packed-Bed Air-Lift Bioreactor.- 5. Serum-Containing Production.- D. Downstream Processing.- E. GMP Production of Retroviral Vectors.- I. Cell Banking.- II. Serum-Free Upstream Processing.- III. Serum-Free Downstream Processing.- F. In-Process Assays.- G. Quality Control.- H. Safety.- I. Summary and Conclusions.- References.- 10 Clinical Systems for the Production of Cells and Tissues for Human Therapy.- A. Introduction.- B. Cell Therapy and Tissue Engineering.- I. Ex Vivo Gene Therapy.- II. Stem-Cell Therapy.- C. Critical Requirements for Ex Vivo Cell Production.- I. Process Reliability and Control: Automation.- II. Process Sterility: Closed Systems.- III. Cell Recovery.- IV. Optimization of Key Culture Parameters by Design.- V. Good Manufacturing Practices.- D. Cell-Culture Devices and Procedures.- I. Traditional Cell-Culture Processes: Research Laboratory Environment.- 1. Culture Flasks and Roller Bottles.- 2. Flexible Tissue Culture Containers.- 3. Bioreactors.- II. AASTROM Cell-Production System.- 1. System Description.- a. Disposable Cell Cassette.- b. Incubator.- c. Processor.- d. System Manager.- e. ID Key.- E. Applications for On-Site Delivery of Therapeutic Cell Production.- I. Bone-Marrow Cell Production.- II. Other Cell and Tissue Production.- F. Summary.- References.