Weert Immunogenicity of Biopharmaceuticals

1. Auflage 2008
ISBN: 978-0-387-75841-1
Verlag: Springer-Verlag
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 266 Seiten

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.

Autoren/Hrsg.

Weert, Marco

Inhaltsverzeichnis

1;Preface;6
2;Contents;8
3;1 Immune Reactions Towards Biopharmaceuticals – a General, Mechanistic Overview;12
3.1;1.1. Introduction;12
3.2;1.2. Antigen Uptake, Processing and Presentation by Antigen Presenting Cells;16
3.3;1.3. Lymphocyte Activation;22
3.4;1.4. Immunological Tolerance;24
3.5;1.5. Self Versus Non-self, the Danger Model and Biopharmaceuticals;27
3.6;1.6. Concluding Remarks;29
4;2 Clinical Aspects of Immunogenicity to Biopharmaceuticals;37
4.1;2.1. Introduction;37
4.2;2.2. Clinical Aspects of Immunogenicity;37
4.3;2.3. Immunogenicity of Biopharmaceuticals in Gene-Defective Hosts;46
4.4;2.4. Adverse Drug Reactions;49
4.5;2.5. Unknown Effects: Glatiramer Acetate;50
4.6;2.6. Treatment of Multiple Sclerosis Patients Who Have Developed Antibodies Against Interferon-ß ;51
4.7;2.7. Conclusions;56
5;3 Assessment of Unwanted Immunogenicity;67
5.1;3.1. Introduction;67
5.2;3.2. Assays for Detection of Antibodies;68
5.3;3.3. Binding Assays;68
5.4;3.4. Cell-Based Neutralization Assays;74
5.5;3.5. Inclusion of Assay Controls for All Antibody Detection Assays;79
5.6;3.6. Practicality of the Assay;79
5.7;3.7. Interpretation and Expression of Results;79
5.8;3.8. Guidance on Optimization, Validation and Standardization of Assays;80
5.9;3.9. Study Strategy;80
5.10;3.10. Conclusions;81
6;4 Models for Prediction of Immunogenicity;84
6.1;4.1. Introduction;84
6.2;4.2. Testing the Immunogenicity of Therapeutic Proteins Using Animals;87
6.3;4.3. Prediction of Immunogenicity Using In Vitro Techniques;89
6.4;4.4. Prediction Using BioInformatics;93
6.5;4.5. Conclusion;98
7;5 Immunogenicity of Biopharmaceuticals: Causes, Methods to Reduce Immunogenicity, and Biosimilars;105
7.1;5.1. Introduction;105
7.2;5.2. Causes of Immunogenicity;105
7.3;5.3. Methods for Reducing Immunogenicity;110
7.4;5.4. Biosimilars;114
7.5;5.5. Conclusions;116
8;6 Case Study: Immunogenicity of rhEPO;120
8.1;6.1. Abstract;120
8.2;6.2. Description of Erythropoietin;120
8.3;6.3. Immune Reactions;122
8.4;6.4. Clinical Relevance and Therapeutic Consequences;124
8.5;6.5. Biosimilars;127
8.6;6.6. Conclusion;129
9;7 Case Study: Immunogenicity of Interferon-Beta;134
9.1;7.1. Abstract;134
9.2;7.2. Introduction;134
9.3;7.3. Description of the IFN Biopharmaceuticals;135
9.4;7.4. Immune Reactions Against IFN-Beta;137
9.5;7.5. Methods of Detection;138
9.6;7.6. Clinical Relevance and Therapeutic Consequences;142
10;8 Case Study: Immunogenicity of Insulin;144
10.1;8.1. Introduction to Diabetes Mellitus and Insulin;144
10.2;8.2. Immunogenicity of Subcutaneously Administered Insulin;146
10.3;8.3. Immunogenicity of Insulin Treatment with Insulin Analogues;146
10.4;8.4. Immunogenicity of Insulin in Special Populations;147
10.5;8.5. Pulmonary Insulin;148
10.6;8.6. Conclusions;150
11;9 Case Study: Immunogenicity of Factor VIII;154
11.1;9.1. Introduction;154
11.2;9.2. Blood Coagulation Factor VIII and Haemophilia A;154
11.3;9.3. Coagulation Factor VIII Concentrates;156
11.4;9.4. Development of Inhibitory Antibodies Against Factor VIII in Haemophilia A;157
11.5;9.5. Clinical Features and Principles of Treatment in Haemophilia Patients with FVIII Inhibitors;163
11.6;9.6. Conclusion;168
12;10 Case Study: Immunogenicity of Natalizumab;179
12.1;10.1. Introduction;179
12.2;10.2. Mechanism of Action of Natalizumab in MS;179
12.3;10.3. Prescribed Use;180
12.4;10.4. Immunogenicity of Natalizumab;181
12.5;10.5. Bioanalytical Assays to Assess Immunogenicity;181
12.6;10.6. Immunogenicity Data from Preclinical Studies;185
12.7;10.7. Immunogenicity Data from Clinical Studies;185
12.8;10.8. Correlation of Immunogenicity with Outcome Measures;187
12.9;10.9. Managing Immunogenicity Risk in Clinical Practice;190
12.10;10.10. Concluding Remarks;191
13;11 Case Study: Immunogenicity of Anti-TNF Antibodies;194
13.1;11.1. Historical Notes;195
13.2;11.2. Anti-TNF Antibody Constructs;196
13.3;11.3. Monitoring Patients Receiving Anti-TNF Antibody Constructs for Compliance, Drug Bioavailability, and Pharmacodynamics;197
13.4;11.4. Immunogenicity of Anti-TNF Antibody Constructs;199
13.5;11.5. Conclusions;205
14;12 Heparin-Induced Thrombocytopenia;209
14.1;12.1. Introduction;209
14.2;12.2. Low Molecular Weight Heparins (LMWHs);214
14.3;12.3. Adverse Effects of Heparin and Low Molecular Weight Heparins;216
14.4;12.4. The Immune-Mediated Response to Heparin;216
14.5;12.5. Treatment;221
14.6;12.6. Conclusion;235
15;13 Presenting an Immunogenicity Risk Assessment to Regulatory Agencies;243
15.1;13.1. Purpose;243
15.2;13.2. Regulatory Guidance;244
15.3;13.3. Risk Assessment;244
15.4;13.4. Key Questions for Risk Assessment;245
15.5;13.5. Common Deficiencies;255
15.6;13.6. Presentation;257
15.7;13.7. Summary;258
16;Subject Index;263

Leseproben

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).