Abstract
The growing demands for existing biologics production are reflected in
biopharmaceutical sales figures: The top 15 products in 2004 posted revenues
of $38 billion. Although biologics manufacturing now is focused chiefly on a
small number of blockbuster products, the future challenges will involve the
ability to gear up for the production of a larger variety of products with
lower sales volumes. D&MD's Bioprocesses of Biopharmaceuticals: The Obligatory
Role of Post Translational Modifications to Create Functional Bioactive
Molecules looks at protein drug manufacturing, starting with choice of methods
and scale-up processes, highlighting important post translational
modifications such as glycosylation.
Table of Contents
Chapter 1: Executive Summary 1�E
Chapter 2: Biopharmaceuticals are Recombinant Products that Replicate
Functions or Antibodies that are Inhibitory 2�E
- Reengineering Medicines 2�E
- Humanized Chimeric Antibodies 2�EEngineered Fusion Proteins𨫎ith and without
Fc 2�E
- PEGylation 2�E
- Glycosylation 2�E0
- Growth Hormones and Enzymes 2�E1
- Human Growth Factors and Enzymes Approved by FDA in 2004 and 2005 2�E2
- Categorization of Growth Factors and Hormones 2�E3
- Therapeutic Antibodies 2�E6
- Economic Considerations of the Commercial Manufacture of Antibodies 2�E7
- Commercialization of Antibody Production 2�E9
- Purification Considerations 2�E1
- Monoclonal Antibody Successes in the Clinic 2�E2
- Antibodies Entering the Clinic 2�E6
- FDA Approval of 18 Therapeutic Antibodies 2�E6
- Therapeutic Approved Antibodies𤋺utside the US 2�E7
- Cytokines嫎 Potential $12�E15 Billion 2005 Market 2�E8
- Survival Factors (SCF, CNTF, BDGF) 2�E9
- FDA Approved Cytokines IL-2 and interferon-alfa 2b and GM-CSF 2�E0
- Interleukin-2 2�E1
- Granulocyte-Monocyte Colony Stimulating Factor 2�E2
- Interleukin-12 2�E2
- Vaccines 2�E2
- Pasteur and the Discovery of Active Immunization 2�E2
- Pediatric Vaccines 2�E5
- Disease Eradication 2�E5
- Cancer Vaccines 2�E7
- Vaccines and Bioterrorism 2�E8
- A Comparison of Pharmaceutical Expression Systems 2�E0
- The Emerging Industry of Plant-Made Pharmaceuticals and Biopharming 2�E3
- Farming Biopharma Drugs䊼rops as Bioreactors 2�E6
- Plant Cell Cultures Currently in Use for Commercial Recombinant
Biopharmaceuticals 2�E9
- Transgenic Animal Factories Cows, Chickens, and Rabbits 2�E2
- Notable Companies Using Transgenics 2�E4
- Process Development 2�E5
Chapter 3: Proteins/Antibodies as Drugs 3�E
- Basic Protein Biochemistry 3�E
- The Amino Acids 3�E
- Chaperone Proteins 3�E
- Protein Structure 3�E
- The Ribosome 3�E1
- Post-Translational Modification 3�E2
- Proteolytic Cleavage 3�E3
- The Coagulation Cascade 3�E4
- Protein Cross Linking 3�E5
- Glycosylation 3�E6
- Biochemistry of Glycosylation 3�E6
- Glycosylated Precursor in the Endoplasmic Reticulum and Golgi Apparatus 3�E8
- Lysosomal Targeting of Enzymes 3�E2
- Clinical Significances of Glycoproteins 3�E2
- Vitamin C-Dependent Modifications 3�E3
- Vitamin K-Dependent Modifications 3�E4
- Acetylation 3�E4
- Phosphorylation 3�E5
- Kinases 3�E6
- Sulfation 3�E6
- Prenylation, Farnesylation, and Geranylgeranylation 3�E8
- Protein Degradation: The Ubiquitin Pathway 3�E0
- Ubiquitin Function 3�E1
- The Ubiquitin-Proteasome Pathway 3�E1
- What are the degradation signals? 3�E1
- How Does Ubiquitination Lead to Protein Degradation? 3�E2
- The Proteasome 3�E3
- The 20S Proteasome Chamber 3�E3
- The Function of the Proteasome 3�E4
- S Proteasome 3�E4
- Proteasomes and the Immune Response 3�E4
- Comparing the Proteasome and Chaperon 3�E5
- Bioreactors for Synthesis of Proteins 3�E5
- Prokaryotic Expression Systems𦝁he Earliest Bioreactor 3�E6
- What is the Future for Bacterial Fermentation? 3�E8
- Single Cell Eukaryotic Based Protein Synthesis 3�E8
- Current Commercial Biopharmaceuticals Made in Yeast and Fungal Expression
Systems 3�E0
- Glycosylation of Therapeutic Proteins 3�E1
- Baculovirus and Insect Cell-Based Protein Synthesis 3�E2
- Mammalian Cell-Based Protein Expression 3�E5
- Hybridomas and at the Production of Monoclonal Antibodies 3�E5
- To Suppress the Immune System 3�E5
- To Kill or Inhibit Malignant Cells 3�E5
- To Block Angiogenesis 3�E6
- Protein Expression in Mammalian Cells 3�E6
- Mammalian Transfection Protocols 3�E8
- Electroporation 3�E9
- Lipofection 3�E9
- Microinjection 3�E9
- Viral Expression Systems 3�E9
- Transient and Stable Transfection𦳀ammalian CHO cells 3�E0
- The Basic Antibody Response 3�E1
- Protein G Based Isolation of Monoclonal Antibody 3�E5
- Uses for Monoclonal Antibodies in Pathology 3�E5
- Transgenic Mice and Phage Display Libraries for Antibody Production 3�E6
- Problems with Monoclonal Therapy 3�E8
- The Science of Transgenes, using Plants and Animals as Drug Factories 3�E1
- How to Make Transgenic Plants 3�E1
- Potential Uses of the Transgenic Plants 3�E2
- Ethical and Political Concerns with Genetically Modified Plants 3�E3
- Transgenic Animals 3�E4
- Nuclear Transfer and Animal Cloning 3�E6
- Nuclear Transfer Technology 3�E6
- Therapeutic Cloning 3�E8
Chapter 4: Quality Control and Post-translational Modifications of
Recombinant Drugs 4�E
- Biopharmaceutical Formulation: Potential Post-Translational Alterations 4�E
- Biotherapeutic Proteins versus Small Molecule Drugs 4�E
- Drug Development Factors for Recombinant Biologicals 4�E
- Critical Factors in Protein Analysis 4�E
- Biologic Stability 4�E0
- Process Development of Recombinant Biologicals 4�E2
- Recombinant Therapeutic Systems 4�E4
- Solubilization of Expressed Recombinants 4�E7
- Glycosylation and Microheterogeneity Affecting Recombinant Drugs 4�E8
- Erythropoietin 4�E0
- Follicular Stimulating Hormone 4�E1
- A Plant's N-glycans Contains �E1,3)-fucose and �E1,2)-xylose 4�E3
- Protein Immunogenicity𡐓eoepitopes 4�E4
- Prenylation and Myristoylation 4�E6
- Vaccine Development 4�E7
- Farensyl Transferase Inhibitors in Cancer 4�E8
- Myristoylated Recombinant Proteins 4�E8
- Phosphorylation of Biopharmaceuticals 4�E9
- Sulfation and Disulfide Bond Formation 4�E1
- Disulfide Bonds and Recombinant Protein Activity/Stability 4�E1
- Thiolation and Sulfation of Therapeutic Proteins 4�E3
- Metabolic Transformations of Biopharmaceuticals 4�E5
- Acetylation and Acylation 4�E6
- Myristyl Acylation 4�E6
- Ubiquitinylation and Proteolytic Processing 4�E7
- Proteolytic Processing of Biopharmaceuticals 4�E9
- Degradomics 4�E0
- Oxidation of Biopharmaceuticals 4�E1
- Deamidation 4�E3
- Glycation of Therapeutic Proteins 4�E6
- Glycomics and Proteomics 4�E7
- Changing Glycosylation in Protein Expression Systems 4�E9
- Glycan-like Formulation Strategies for Protein Pharmaceuticals 4�E0
Chapter 5: Protection of Biopharmaceutical Products 5�E
- Recent Problems with Counterfeited Drugs𡐓ational Association of Boards of
Pharmacy Potential List of Counterfeit Medicines 5�E
- Anti-Counterfeiting Measures for Biopharmaceutical Brand Protection 5�E
- Financial Loss 5�E
- Brand Damage 5�E
- Organized Crime 5�E
- Terrorism 5�E
- Covert, Overt, and Forensic Solutions 5�E
- Nonprinted Security Features 5�E
Chapter 6: Products of the Leading Biopharmaceutical Companies 6�E
- Amgen Inc. 6�E
- Biogen Idec, Inc. 6�E
- Genentech, Inc. 6�E
- Serono, Inc. 6�E
- Eli Lilly and Company 6�E0
- Roche 6�E2
- Biogeneric娋iopharmaceutical Generics 6�E3
- The Hatch Waxman Act 6�E4
- US FDA Regulations 6�E4
- Invalidation of Amgen Patent for EPO in UK 6�E6
- Conclusions�E005 Sales Patterns 6�E9
- Overview 6�E1
TABLE OF EXHIBITS
- Exhibit 2.1 Biopharmaceuticals Approved and in the Market Through 2003 2�E
- Exhibit 2.2 Recent Chimeric Approved Antibodies To Date 2�E
- Exhibit 2.3 Humanized Antibodies in Clinical Trials in 2005 2�E
- Exhibit 2.4 FDA Approved Growth Hormones and Enzymes in 2004 and 2005 2�E2
- Exhibit 2.5 Summary of Growth Factors in R&D Stages 2�E3
- Exhibit 2.6 Flow Chart of Fundamental Steps in a Culture/bioreactor
Product 2�E1
- Exhibit 2.7 US and Europe Approved Therapeutic Antibodies Until 2005 2�E3
- Exhibit 2.8 2004 and 2005 FDA-approved Antibodies 2�E5
- Exhibit 2.9 Number of Therapeutic Monoclonal Antibodies Entering the
Clinic from 1984 to 2004 2�E6
- Exhibit 2.10 Bacterial/Viral Infections Targets for Vaccines 2�E7
- Exhibit 2.11 Types of Cancer Vaccines in Development 2�E8
- Exhibit 2.12 Companies Involved in Bioterror Vaccine Production 2�E0
- Exhibit 2.13 Advantages and Disadvantages of Different Expression Systems
2�E2
- Exhibit 2.14 Plant-derived Pharmaceuticals Close to Commercialization 2�E4
- Exhibit 2.15 Biotech Companies Specializing in Plant Made Pharmaceuticals
2�E8
- Exhibit 2.16 Expression Hosts and Yields of Recombinant Proteins in
Production 2�E0
- Exhibit 2.17 From a Transgenic Plants to a Commercial Product 2�E2
- Exhibit 2.18 Companies Involved in the Manufacture of Biopharmaceuticals
2�E5
- Exhibit 3.1 An Amino Acid 3�E
- Exhibit 3.2 The Peptide Bond in a Protein 3�E
- Exhibit 3.3 Amino Acids are Stereoisomers 3�E
- Exhibit 3.4 The 20 Naturally Occurring Amino Acids 3�E
- Exhibit 3.5 Hsp60 Chaperone Protein Crystal Structure 3�E
- Exhibit 3.6 Four Levels of Protein Structure 3�E
- Exhibit 3.7 Secondary Structure 3�E
- Exhibit 3.8 The Central Dogma 3�E0
- Exhibit 3.9 Transfer RNA 3�E0
- Exhibit 3.10 The Genetic Code 3�E1
- Exhibit 3.11 Protein Synthesis on the Ribosome 3�E2
- Exhibit 3.12 Common Post-Translational Modifications of Proteins 3�E3
- Exhibit 3.13 Cleavage Sites of Common Proteases 3�E4
- Exhibit 3.14 The Coagulation Cascade 3�E5
- Exhibit 3.15 The Amino Acid Cysteine Creates Disulfide Linkages 3�E6
- Exhibit 3.16 The Ring Structure of Monosaccharides 3�E7
- Exhibit 3.17 Common Monosaccharides and Disaccharides 3�E7
- Exhibit 3.18 The Glycosidic Bond 3�E8
- Exhibit 3.19 O Linked Carbohydrates 3�E0
- Exhibit 3.20 N Linked Carbohydrates 3�E1
- Exhibit 3.21 Dolichol Structure 3�E2
- Exhibit 3.22 Enzyme Defects in Degradation of Asn-GlcNAc Type
Glycoproteins 3�E3
- Exhibit 3.23 Structure of a Gla Residue 3�E4
- Exhibit 3.24 The Universal PAPS Reaction 3�E7
- Exhibit 3.25 Protein Prenylation 3�E9
- Exhibit 3.26 The Proteasome 3�E3
- Exhibit 3.27 Bioreactors for Protein Production 3�E6
- Exhibit 3.28 Advantages of an Expression System Using Protozoa 3�E9
- Exhibit 3.29 Yeasts S. Serevisiae and P. Pastoris Therapeutic Protein
Production 3�E2
- Exhibit 3.30 Baculovirus Expression System 3�E4
- Exhibit 3.31 Mammalian Transfection and Expression Protocol 3�E7
- Exhibit 3.32 Mammalian Expression Vector 3�E8
- Exhibit 3.33 Basic Techniques for Creating Hybridomas 3�E2
- Exhibit 3.34 Monoclonal Antibodies used in Pathology 3�E5
- Exhibit 3.35 Panning of Phage Libraries 3�E7
- Exhibit 3.36 Basic Antibody Structure 3�E8
- Exhibit 3.37 Cancer Clinical Trails using Monoclonal Antibodies till June,
2005 3�E0
- Exhibit 3.38 Current Genetically Modified Plant Studies 3�E2
- Exhibit 3.39 Microinjection for Creating Transgenic Animals 3�E4
- Exhibit 3.40 Microinjection Process 3�E5
- Exhibit 3.41 Breeding Protocol to Produce Homozygote Transgenic Animals 3�E5
- Exhibit 3.42 Drugs Currently Synthesized in Transgenic Animals 3�E6
- Exhibit 3.43 Cloning of Livestock 3�E7
- Exhibit 3.44 Therapeutic Cloning Protocol 3�E9
- Exhibit 4.1 FDA's Division of Therapeutic Proteins (DTP) Product Diversity
4�E
- Exhibit 4.2 Recombinant Protein Analysis Solutions 4�E
- Exhibit 4.3 Successful Isolation of a Recombinant Antitumor Immunoreagent
4�E0
- Exhibit 4.4 Shelf Life of Recombinant Protein Drugs 4�E1
- Exhibit 4.5 Stability-Indicating Test Methods for Recombinant Proteins 4�E1
- Exhibit 4.6 Solubilization Strategies for Expressed Recombinants 4�E8
- Exhibit 4.7 Microheterogeneity of FSH 4�E2
- Exhibit 4.8 Ubiquitinylation of Therapeutic Protein 4�E8
- Exhibit 4.9 Protein Oxidation Reactions 4�E2
- Exhibit 4.10 Protein Deamidation 4�E3
- Exhibit 5.1 Counterfeited Nutropin Vials 5�E
- Exhibit 5.2 NABP's list of Susceptible Products 5�E
- Exhibit 5.3 Anticounterfeiting Security Measures 5�E
- Exhibit 6.1 Amgen's Lead Biopharmaceuticals 6�E
- Exhibit 6.2 Biogen's Lead Biopharmaceuticals 6�E
- Exhibit 6.3 Genentech's Lead Biopharmaceuticals 6�E
- Exhibit 6.4 Serono's Lead Biopharmaceuticals 6�E
- Exhibit 6.5 Lilly's Lead Biopharmaceuticals 6�E1
- Exhibit 6.6 Top Biopharmaceuticals and Their Patent Positions in 2000 6�E6
- Exhibit 6.7 Disease Targets for Biopharmaceuticals 6�E1
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