Immunogenicity of Biopharmaceuticals (eBook)

Eva Horn Moller, Marco Weert (Herausgeber)

eBook Download: PDF

2008 | 2008
XII, 266 Seiten
Springer New York (Verlag)
978-0-387-75841-1 (ISBN)

Infos

Immunogenicity of Biopharmaceuticals is the first book to comprehensively address the potential of an immune response to biopharmaceuticals. It is intended to give a broad overview of the current state-of-the-art regarding this subject. The chapters range from an overview of the immune system and factors that may trigger the immune system, via detection of antibodies and clinical implications, to various case examples and the regulatory view on immunogenicity.

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A particular issue for biopharmaceuticals that has not been addressed comprehensively in any book, is the potential of an immune response to the biopharmaceutical product. That is, the human body marks the drug as a foreign body, and develops antibodies against the drug. These antibodies may be relatively harmless, but may also cross-react with the endogenous compound, causing autoimmunogenicity. Recent adverse experiences in Europe with Janssen-Ortho's blockbuster product Eprex has increased the attention towards potential immunogenicity of biopharmaceuticals, above all from the regulatory agencies.This book is intended to give a broad overview of the current state-of-the-art regarding the immune response to biopharmaceuticals. The chapters range from an overview of the immune system and factors that may trigger the immune system, via detection of antibodies and clinical implications, to various case examples and the regulatory view on immunogenicity.

Inhalt

Preface 6
Contents 8
1 Immune Reactions Towards Biopharmaceuticals – a General, Mechanistic Overview 12
1.1. Introduction 12
1.2. Antigen Uptake, Processing and Presentation by Antigen Presenting Cells 16
1.3. Lymphocyte Activation 22
1.4. Immunological Tolerance 24
1.5. Self Versus Non-self, the Danger Model and Biopharmaceuticals 27
1.6. Concluding Remarks 29
2 Clinical Aspects of Immunogenicity to Biopharmaceuticals 37
2.1. Introduction 37
2.2. Clinical Aspects of Immunogenicity 37
2.3. Immunogenicity of Biopharmaceuticals in Gene-Defective Hosts 46
2.4. Adverse Drug Reactions 49
2.5. Unknown Effects: Glatiramer Acetate 50
2.6. Treatment of Multiple Sclerosis Patients Who Have Developed Antibodies Against Interferon-ß 51
2.7. Conclusions 56
3 Assessment of Unwanted Immunogenicity 67
3.1. Introduction 67
3.2. Assays for Detection of Antibodies 68
3.3. Binding Assays 68
3.4. Cell-Based Neutralization Assays 74
3.5. Inclusion of Assay Controls for All Antibody Detection Assays 79
3.6. Practicality of the Assay 79
3.7. Interpretation and Expression of Results 79
3.8. Guidance on Optimization, Validation and Standardization of Assays 80
3.9. Study Strategy 80
3.10. Conclusions 81
4 Models for Prediction of Immunogenicity 84
4.1. Introduction 84
4.2. Testing the Immunogenicity of Therapeutic Proteins Using Animals 87
4.3. Prediction of Immunogenicity Using In Vitro Techniques 89
4.4. Prediction Using BioInformatics 93
4.5. Conclusion 98
5 Immunogenicity of Biopharmaceuticals: Causes, Methods to Reduce Immunogenicity, and Biosimilars 105
5.1. Introduction 105
5.2. Causes of Immunogenicity 105
5.3. Methods for Reducing Immunogenicity 110
5.4. Biosimilars 114
5.5. Conclusions 116
6 Case Study: Immunogenicity of rhEPO 120
6.1. Abstract 120
6.2. Description of Erythropoietin 120
6.3. Immune Reactions 122
6.4. Clinical Relevance and Therapeutic Consequences 124
6.5. Biosimilars 127
6.6. Conclusion 129
7 Case Study: Immunogenicity of Interferon-Beta 134
7.1. Abstract 134
7.2. Introduction 134
7.3. Description of the IFN Biopharmaceuticals 135
7.4. Immune Reactions Against IFN-Beta 137
7.5. Methods of Detection 138
7.6. Clinical Relevance and Therapeutic Consequences 142
8 Case Study: Immunogenicity of Insulin 144
8.1. Introduction to Diabetes Mellitus and Insulin 144
8.2. Immunogenicity of Subcutaneously Administered Insulin 146
8.3. Immunogenicity of Insulin Treatment with Insulin Analogues 146
8.4. Immunogenicity of Insulin in Special Populations 147
8.5. Pulmonary Insulin 148
8.6. Conclusions 150
9 Case Study: Immunogenicity of Factor VIII 154
9.1. Introduction 154
9.2. Blood Coagulation Factor VIII and Haemophilia A 154
9.3. Coagulation Factor VIII Concentrates 156
9.4. Development of Inhibitory Antibodies Against Factor VIII in Haemophilia A 157
9.5. Clinical Features and Principles of Treatment in Haemophilia Patients with FVIII Inhibitors 163
9.6. Conclusion 168
10 Case Study: Immunogenicity of Natalizumab 179
10.1. Introduction 179
10.2. Mechanism of Action of Natalizumab in MS 179
10.3. Prescribed Use 180
10.4. Immunogenicity of Natalizumab 181
10.5. Bioanalytical Assays to Assess Immunogenicity 181
10.6. Immunogenicity Data from Preclinical Studies 185
10.7. Immunogenicity Data from Clinical Studies 185
10.8. Correlation of Immunogenicity with Outcome Measures 187
10.9. Managing Immunogenicity Risk in Clinical Practice 190
10.10. Concluding Remarks 191
11 Case Study: Immunogenicity of Anti-TNF Antibodies 194
11.1. Historical Notes 195
11.2. Anti-TNF Antibody Constructs 196
11.3. Monitoring Patients Receiving Anti-TNF Antibody Constructs for Compliance, Drug Bioavailability, and Pharmacodynamics 197
11.4. Immunogenicity of Anti-TNF Antibody Constructs 199
11.5. Conclusions 205
12 Heparin-Induced Thrombocytopenia 209
12.1. Introduction 209
12.2. Low Molecular Weight Heparins (LMWHs) 214
12.3. Adverse Effects of Heparin and Low Molecular Weight Heparins 216
12.4. The Immune-Mediated Response to Heparin 216
12.5. Treatment 221
12.6. Conclusion 235
13 Presenting an Immunogenicity Risk Assessment to Regulatory Agencies 243
13.1. Purpose 243
13.2. Regulatory Guidance 244
13.3. Risk Assessment 244
13.4. Key Questions for Risk Assessment 245
13.5. Common Deficiencies 255
13.6. Presentation 257
13.7. Summary 258
Subject Index 263

Textauszug

4 Models for Prediction of Immunogenicity (p. 75-76)

Erwin L. Roggen

4.1. Introduction

4.1.1. Mechanisms of Immunogenicity

Any foreign substance will trigger the highly organised and regulated innate and adaptive networks of cells, and soluble (e.g. antibodies, cytokines) and membrane-associated molecules (e.g. receptors, co-stimulatory factors) that have developed throughout evolution to protect man against phylogenetic distant organisms, and their products. These mechanisms have been extensively reviewed elsewhere (Chapter 1). Therefore, the following paragraphs will only highlight those components of the immune system with relevance to this chapter.

4.1.1.1. The Innate Response

The innate immune system constitutes the primary line of defense. Although non-specific and not conferring long-lasting immunity, a good understanding of these defences is imperative for a proper description of protein immunogenicity as several components of the innate response link innate and adaptive immune networks.

There is growing evidence suggesting that epithelial cells (EC) in the skin and mucosal linings play a critical role in homeostasis and host defence reactions (McKenzie and Sauder 1990, Lambrecht and Hammad 2003a).

Trauma of these linings will induce inflammation, a process characterised by release, among others, of eicosanoids (e.g. prostaglandins and leukotrienes) and a variety of cytokines (e.g. interleukin (IL)-1, IL-6, IL-8) by the affected cells, recruitment of innate leukocytes, removal of the offending compound and healing of any damaged tissue (Hietbrink et al. 2006).

Complement is the major humoral component of the innate immune response. In humans, this response is activated by the binding of complement proteins to carbohydrate structures on micro-organisms or by complement binding to antibodies that have attached to such micro-organisms. The result of these interactions is a rapid killing response, resulting in the production of peptides that, among others, attract immune cells (Rus, Cudrici and Niculescu 2005). The relevance of complement-mediated processes for protein immunogenicity is demonstrated by the occurrence of adverse complement-mediated cell lysis induced by specific or cross-reacting IgM and IgG antibody recognising membrane-associated self-antigen or foreign protein adsorbed to the cell surface (Silverstein 1989).

The innate leukocytes include phagocytic cells, among others macrophages, neutrophils and dendritic cells (DC). During the acute phase of inflammation, circulating neutrophils migrate towards the site of inflammation and are usually the first cells to arrive at the affected tissue. Upon arrival, these cells will release a number of factors which further enhance epithelial IL-1 and IL-8 production, resulting in the excretion of the chemokine CCL20 known to attract immature DC (Roggen et al. 2006). Macrophages are versatile cells that reside within tissues and express a phenotype that is generated by the tissue micro-environment (e.g. by EC, fibroblasts and endothelial cells) (Striz et al. 2001). They produce a wide array of enzymes, complement proteins and regulatory factors (e.g. IL-1), and they have the capability to function as antigen-presenting cells. Thus, macrophages determine the outcome of immune responses by instructing both the innate and the adaptive immune systems. Evidence has been presented showing that macrophages with disregulated phenotype are involved in the induction of auto-immunity and allergic sensitisation (Thepen, Kraal and Holt 1996, Stoy 2001, Chen et al. 2003).

DC are phagocytes in tissues that are in contact with the external environment (e.g. skin and mucosal linings). Like macrophages, DC link the innate and adaptive immune systems through their antigen-presenting activity and are recognised to play a role in adverse immune responses (Guermonprez et al. 2002, Lambrecht and Hammad 2003b).

Produkt-Details

• Erscheint lt. Verlag: 6.2.2008
• Reihe/Serie: Biotechnology: Pharmaceutical Aspects
• Zusatzinfo: XII, 266 p.
• Verlagsort: New York
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Gesundheitsfachberufe
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie
• Themenwelt: Medizin / Pharmazie ► Pharmazie
• Themenwelt: Studium ► Querschnittsbereiche ► Infektiologie / Immunologie
• Themenwelt: Technik ► Umwelttechnik / Biotechnologie
• Schlagworte: Biosimilar • Drug • Interferon • Pharmaceutical • Reaction • Research
• ISBN-10: 0-387-75841-0 / 0387758410
• ISBN-13: 978-0-387-75841-1 / 9780387758411