Weert / Møller Immunogenicity of Biopharmaceuticals

1. Auflage 2008
ISBN: 978-0-387-75841-1
Verlag: Springer US
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band VIII, 266 Seiten, eBook

Reihe: Biotechnology: Pharmaceutical Aspects

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.

Zielgruppe

Research

Autoren/Hrsg.

Weert, Marco

Møller, Eva Horn

Inhaltsverzeichnis

Immune Reactions Towards Biopharmaceuticals – a General, Mechanistic Overview.- Clinical Aspects of Immunogenicity to Biopharmaceuticals.- Assessment of Unwanted Immunogenicity.- Models for Prediction of Immunogenicity.- Immunogenicity of Biopharmaceuticals: Causes, Methods to Reduce Immunogenicity, and Biosimilars.- Case Study: Immunogenicity of rhEPO.- Case Study: Immunogenicity of Interferon-Beta.- Case Study: Immunogenicity of Insulin.- Case Study: Immunogenicity of Factor VIII.- Case Study: Immunogenicity of Natalizumab.- Case Study: Immunogenicity of Anti-TNF Antibodies.- Heparin-Induced Thrombocytopenia.- Presenting an Immunogenicity Risk Assessment to Regulatory Agencies.

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).