Assessment of Dextran Antigenicity of Intravenous Iron Preparations with Enzyme-Linked Immunosorbent Assay (ELISA).

Susann Neiser,Maria Wilhelm,Susanna Burckhardt,Taija Koskenkorva,Katrin Schwarz

doi:10.3390/ijms17071185

Susann Neiser, Maria Wilhelm + Show 3 more

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https://doi.org/10.3390/ijms17071185

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Abstract

Intravenous iron preparations are typically classified as non-dextran-based or dextran/dextran-based complexes. The carbohydrate shell for each of these preparations is unique and is key in determining the various physicochemical properties, the metabolic pathway, and the immunogenicity of the iron-carbohydrate complex. As intravenous dextran can cause severe, antibody-mediated dextran-induced anaphylactic reactions (DIAR), the purpose of this study was to explore the potential of various intravenous iron preparations, non-dextran-based or dextran/dextran-based, to induce these reactions. An IgG-isotype mouse monoclonal anti-dextran antibody (5E7H3) and an enzyme-linked immunosorbent assay (ELISA) were developed to investigate the dextran antigenicity of low molecular weight iron dextran, ferumoxytol, iron isomaltoside 1000, ferric gluconate, iron sucrose and ferric carboxymaltose, as well as isomaltoside 1000, the isolated carbohydrate component of iron isomaltoside 1000. Low molecular weight iron dextran, as well as dextran-based ferumoxytol and iron isomaltoside 1000, reacted with 5E7H3, whereas ferric carboxymaltose, iron sucrose, sodium ferric gluconate, and isolated isomaltoside 1000 did not. Consistent results were obtained with reverse single radial immunodiffusion assay. The results strongly support the hypothesis that, while the carbohydrate alone (isomaltoside 1000) does not form immune complexes with anti-dextran antibodies, iron isomaltoside 1000 complex reacts with anti-dextran antibodies by forming multivalent immune complexes. Moreover, non-dextran based preparations, such as iron sucrose and ferric carboxymaltose, do not react with anti-dextran antibodies. This assay allows to assess the theoretical possibility of a substance to induce antibody-mediated DIARs. Nevertheless, as this is only one possible mechanism that may cause a hypersensitivity reaction, a broader set of assays will be required to get an understanding of the mechanisms that may lead to intravenous iron-induced hypersensitivity reactions.

Highlights

Iron is an essential component of the body
In the newly developed enzyme-linked immunosorbent assay (ELISA) assay, a positive result was defined as at 450 nm (A450) ratio ě2.1
Two different in vitro assays showed that, in addition to low molecular weight iron dextran (LMWID), dextran-based IV iron preparations FMX and iron isomaltoside 1000 (IIM) react with anti-dextran antibody, suggesting that antibody-mediated dextran-induced anaphylactic reactions (DIAR) can occur in vivo

Summary

Introduction

When present in excess, iron is toxic [1] and has the potential to induce oxidative stress [2]. Because IV administration bypasses the strictly regulated iron absorption in the gut, it is critical that IV iron preparations are engineered to deliver high doses of iron in a stable, non-reactive and non-toxic form. All preparations for IV iron therapy are composed of carbohydrate-stabilized polynuclear iron(III)-oxyhydroxide/oxide nanoparticles formulated as colloidal solutions. They are non-biological complex drugs (NBCDs) [5,6]. In addition to stabilizing the iron core in a ligand-specific way, the shell is the key component regulating the stability, size, shape and surface charge of the iron-carbohydrate complex [2]. Upon IV administration, the carbohydrate shell determines the metabolic pathway of the complexes, affecting their pharmacokinetics and pharmacodynamics, as well as their interaction with the innate immune system and, side effects [2]

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