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Pharm Res (2011) 28:23792385 DOI 10.1007/s11095-011-0523-5
The Author(s) 2011. This article is published with open access at Springerlink.com
EXPERT REVIEW
Immunogenicity of Therapeutic Proteins: The Use of Animal Models
Vera Brinks & Wim Jiskoot & Huub Schellekens
Received: 23 March 2011 /Accepted: 27 June 2011 /Published online: 9 July 2011 #
ABSTRACT Immunogenicity of therapeutic proteins lowers patient well-being and drastically increases therapeutic costs. Preventing immunogenicity is an important issue to consider when developing novel therapeutic proteins and applying them in the clinic. Animal models are increasingly used to study immunogenicity of therapeutic proteins. They are employed as predictive tools to assess different aspects of immunogenicity during drug development and have become vital in studying the mechanisms underlying immunogenicity of therapeutic proteins. However, the use of animal models needs critical evaluation. Because of species differences, predictive value of such models is limited, and mechanistic studies can be restricted. This review addresses the suitability of animal models for immunogenicity prediction and summarizes the insights in immunogenicity that they have given so far.
KEY WORDS animal models . immunogenicity. therapeutic proteins
ABBREVIATIONSBLAST basic local alignment search tool CD cluster of differentiationHLA human leucocyte antigenMHC major histocompatibility complex PEG polyethylene glycolPLGA poly(lactide-co-glycolide)tPA tissue plasminogen activator
INTRODUCTION
Therapeutic proteins have revolutionized the treatment of diseases such as diabetes, multiple sclerosis and rheumatoid arthritis. An advantage of these drugs is that they do not possess intrinsic toxicity due to harmful metabolites; they are broken down to amino acids (1). Furthermore, therapeutic proteins are highly versatile. By recombinant DNA techniques, monoclonal antibodies can be designed to bind to various endogenous molecules in order to affect their function. As a result, therapeutic proteins now make up around 30% of the marketed drugs, and many more are under development.
Immunogenicity is a major disadvantage of these protein drugs. Almost all therapeutic proteins induce an antibody response (2). While such an antibody response does not necessarily cause severe side effects, clinical implications can occur. Antibody formation may lead to a loss of efficacy, neutralization of the endogenous counterpart or general immune system effects (i.e., serum sickness like disease, infusion reactions, anaphylaxis and anaphylactoid reactions) (36). To prevent antibody-induced side effects and thereby warrant better patient well-being and lower therapeutic costs, it is important to...