Evaluation of the Cross-reactivity of Antidrug Antibodies to CT-P13 and Infliximab Reference Product (Remicade): An Analysis Using Immunoassays Tagged with Both Agents

Abstract

BackgroundDuring two pivotal clinical trials of the infliximab biosimilar CT-P13 (PLANETAS and PLANETRA), antidrug antibodies (ADAs) and neutralising antibodies (NAbs) were detected in the sera of patients treated with CT-P13 and the reference product (RP; Remicade).ObjectiveThe aim was to assess the comparability of Remicade- and CT-P13-tagged immunoassays for the detection of ADAs and NAbs using data from these trials, in order to determine the cross-reactivity of CT-P13 and RP ADAs.MethodsSera from patients with rheumatoid arthritis and ankylosing spondylitis were analysed using an electrochemiluminescence (ECL) bridging assay or Gyros immunoassay, tagged with Remicade or CT-P13 at screening, weeks 14, 30 and 54, and the end of study visit. NAb titre was compared at screening and weeks 14 and 30. The proportion of cross-reactive samples was determined and an inter-rater agreement analysis performed to assess the concordance of results between assays.ResultsIn PLANETAS, 93.1% (94/101) of RP ADA-positive samples and 93.0% (93/100) of RP NAb-positive samples cross-reacted with CT-P13; 99.0% (103/104) of CT-P13 ADA-positive and 98.0% (98/100) of CT-P13 NAb-positive samples cross-reacted with the RP. In PLANETRA, 94.7% (426/450) of RP ADA-positive samples and 94.3% (415/440) of RP NAb-positive samples cross-reacted with CT-P13, and 96.6% (458/474) of CT-P13 ADA-positive and 96.4% (452/469) of CT-P13 NAb-positive samples cross-reacted with the RP. In both studies, there was strong agreement in outcome between assays at all post-screening time points (PLANETAS: Cohen’s κ 0.89–0.98 for ADA, 0.86–0.98 for NAb; PLANETRA: 0.92–0.94 for both ADA and NAb, all p < 0.001). Significant concordance between assays was observed for NAb titre at weeks 14 and 30 (PLANETAS: Spearman’s ρ 0.73 and 0.74, respectively; PLANETRA: 0.61 and 0.72, respectively; all p < 0.001).ConclusionsThis study has demonstrated that ADAs and NAbs against CT-P13 and RP are cross-reactive, indicating that CT-P13 and RP share immunodominant epitopes.Electronic supplementary materialThe online version of this article (doi:10.1007/s40259-017-0219-4) contains supplementary material, which is available to authorized users.

The Efficacy, Safety, and Immunogenicity of Switching Between Reference Biopharmaceuticals and Biosimilars: A Systematic Review

“…Several studies have investigated the immunogenic profile of the infliximab RP and one of its biosimilars CT-P13 (Remsima/ Inflectra) and the cross-reactivity of ADAs between both products. 7,[78][79][80] These studies provided similar results in support of the immunogenic similarity between the infliximab RP and CT-P13 in IBD 80,78 or rheumatic diseases. 7,79 It was shown that ADAs against the RP recognized and reacted to the biosimilar in a similar way, indicating that these products share similar immunodominant epitopes.…”

“…7,[78][79][80] These studies provided similar results in support of the immunogenic similarity between the infliximab RP and CT-P13 in IBD 80,78 or rheumatic diseases. 7,79 It was shown that ADAs against the RP recognized and reacted to the biosimilar in a similar way, indicating that these products share similar immunodominant epitopes. Additional epitopes (e.g., due to differences in the glycosylation pattern, impurities, or aggregations) may not be excluded, but data suggest that the epitopes that are involved in the immune response to the RP are also present for CT-P13.…”

Demonstrating Biosimilar and Originator Antidrug Antibody Binding Comparability in Antidrug Antibody Assays: A Practical Approach

“…The pros and cons are briefly discussed in the above literature analysis. A notable published case example to support the use of the one-assay approach is Remsima ® where both the one-and two-assay approaches were applied without any difference in outcome [22]. Based on our experiences in various biosimilar programs, we view using the biosimilar as labeling reagent and also as confirmatory quenching reagent in a one-assay approach as a conservative strategy suitable for a similarity immunogenicity exercise.…”

Biosimilar and interchangeable: Inseparable scientific concepts?

“…However, the stringent scientific proof of physicochemical and functional comparability is also key to substantiating the conclusion of equivalent immunogenicity. Conclusive molecular overlap between biosimilars and reference medicines is well‐illustrated by the finding that anti‐drug antibodies (ADA) cross‐react equally with both products . Although analytical comparability is reassuring on its own, reference regulatory bodies require case‐by‐case, pre‐ and post‐authorization immunogenicity‐targeted assessment plans .…”

“…Conclusive molecular overlap between biosimilars and reference medicines is well-illustrated by the finding that anti-drug antibodies (ADA) cross-react equally with both products. 17 Although analytical comparability is reassuring on its own, reference regulatory bodies require caseby-case, pre-and post-authorization immunogenicity-targeted assessment plans. 18 Accordingly, over many years of pharmaceutical surveillance of biosimilar safety and efficacy in European countries, including switching scenarios in Nordic countries 15,19 and more recently in the United Kingdom, 20 no unexpected alerts or warnings have been raised regarding the development of ADA, or any other adverse effect, as a result of the presence of biosimilars on the market.…”