Background Anti drug antibodies are known to alter drug pharmacokinetics, decrease drug efficacy and in rare cases they may also lead to life-threatening anaphylactic or anaphylactoid reactions. Infliximab is a chimeric monoclonal antibody that is due to its variable domains of murine origin often immunogenic for its recipients. Previously, we reported that antibodies to infliximab (ATI) developed in nearly 43% of the pediatric patients with rheumatic diseases that were treated with infliximab. The development of ATI was in all cases associated with decreased infliximab serum trough levels and decreased drug efficacy (Kosmač et al., 2011).
Objectives In the present study we analyzed the isotypes (IgG, IgM, IgA and IgE) and in the case of IgG antibodies also the subtypes (IgG1, IgG2, IgG3 and IgG4) of ATI-positive serum samples from pediatric patients treated with infliximab.
Methods We compared the isotype-specific binding assay with the more common double antigen bridging assay and used both to analyze 121 serum samples from 21 pediatric patients treated with infliximab. In the 36 serum samples that tested positive for ATI in the isotype-specific binding assay we also used this assay to subsequently determine the isotypes and IgG subtypes of the detected antibodies.
Results The predominant ATI isotype was IgG (median [IQR] =60.5% [65.4%]), followed by IgA (35.4% [65.5%]), IgE (0.8% [0.9%]) and IgM (bellow detection). More specifically, the two most represented IgG subtypes were IgG1 and IgG3 (27.9% [52.9%] and 20.4% [38.6%] of total IgG, respectively). However, in the majority of sera tested several different isotypes and subtypes were observed simultaneously and in the cases where high absolute ATI values were observed there was a high proportion of IgG4 (30.6% [13.8%]).
Conclusions As expected for T-dependent protein antigens, ATI were predominantly of the IgG isotype. There was a low prevalence of IgE antibodies, also in the cases where patients experienced infusion-related reactions, arguing against the classical type I hypersensitivity. After IgG, the second most prominent anti-infliximab isotype were IgA antibodies, which are generally not regarded as a clinically significant antibody isotype, but may along with IgG4 play an immunoprotective role in the chronic exposure to a specific antigen.
Additionally, we found that the isotype-specific binding assay was faster, more sensitive and less influenced by residual drug interference than the more common bridging assay. It is however, more prone to false positive results and should therefore be employed in the screening phase of ADA determination.
Kosmač, M., Avčin, T., Toplak, N., Simonini, G., Cimaz, R. and Čurin Šerbec, V., 2011. Exploring the binding sites of anti-infliximab antibodies in pediatric patients with rheumatic diseases treated with infliximab. Pediatric Research, 69(3), pp. 243-248.
Disclosure of Interest None Declared
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