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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Immunol. Mar 27, 2016; 6(1): 19-38
Published online Mar 27, 2016. doi: 10.5411/wji.v6.i1.19
Maillard reaction and immunogenicity of protein therapeutics
Rositsa Tsekovska, Angelina Sredovska-Bozhinov, Toshimitsu Niwa, Ivan Ivanov, Roumyana Mironova
Rositsa Tsekovska, Ivan Ivanov, Roumyana Mironova, Institute of Molecular Biology Roumen Tsanev, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
Angelina Sredovska-Bozhinov, MIT University, 1000 Skopje, Macedonia
Toshimitsu Niwa, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Author contributions: Tsekovska R and Sredovska-Bozhinov A contributed equally to this work; Mironova R, Niwa T and Ivanov I designed the research; Tsekovska R and Sredovska-Bozhinov A performed the research; Tsekovska R, Sredovska-Bozhinov A and Mironova R wrote the paper; Niwa T and Ivanov I reviewed the paper.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Roumyana Mironova, Professor, Institute of Molecular Biology Roumen Tsanev, Bulgarian Academy of Sciences, Acad. G. Bonchev str., bl. 21, 1113 Sofia, Bulgaria. rumym@bio21.bas.bg
Telephone: +359-2979-2648 Fax: +359-2872-3507
Received: June 27, 2015
Peer-review started: June 29, 2015
First decision: November 6, 2015
Revised: November 24, 2015
Accepted: December 13, 2015
Article in press: January 4, 2016
Published online: March 27, 2016
Abstract

The recombinant DNA technology enabled the production of a variety of human therapeutic proteins. Accumulated clinical experience, however, indicates that the formation of antibodies against such proteins is a general phenomenon rather than an exception. The immunogenicity of therapeutic proteins results in inefficient therapy and in the development of undesired, sometimes life-threatening, side reactions. The human proteins, designed for clinical application, usually have the same amino acid sequence as their native prototypes and it is not yet fully clear what the reasons for their immunogenicity are. In previous studies we have demonstrated for the first time that interferon-β (IFN-β) pharmaceuticals, used for treatment of patients with multiple sclerosis, do contain advanced glycation end products (AGEs) that contribute to IFN-β immunogenicity. AGEs are the final products of a chemical reaction known as the Maillard reaction or glycation, which implication in protein drugs’ immunogenicity has been overlooked so far. Therefore, the aim of the present article is to provide a comprehensive overview on the Maillard reaction with emphasis on experimental data and theoretical consideration telling us why the Maillard reaction warrants special attention in the context of the well-documented protein drugs’ immunogenicity.

Keywords: Maillard reaction, Glycation, Advanced glycation end products, Protein therapeutics, Interferon-β, Immunogenicity

Core tip: The Maillard reaction occurs spontaneously in host cells and causes covalent modifications, proteolysis and crosslinking of therapeutic proteins. These are gross structural changes, which upon administration may provoke in patients classical type innate and adaptive immune responses. The consequences of the Maillard reaction, however, reach far beyond. Specific and non-specific cellular receptors for the advanced products of the Maillard reaction may further enhance the immune response and elicit inflammation. All together the Maillard reaction actions are expected to result in drug neutralization and side effects in treated patients such as inflammatory and hypersensitivity reactions.