Second-Generation Biologics Show Better TNF-Neutralizing Capabilities, Study Finds

Kelly Davio

Second-generation anti–tumor necrosis factor (TNF) agents, etanercept, certolizumab, and golimumab, demonstrated a stronger neutralizing effect toward TNF versus first-generation anti-TNF agents, infliximab and adalimumab.

Anti—tumor necrosis factor (TNF) agents such as infliximab and adalimumab are widely used to treat inflammatory diseases but approximately 10% to 21% of patients annually lose response to treatment because of the development of anti-drug antibodies (ADAs). In a paper newly published in Plos One, researchers sought to examine whether anti-infliximab antibodies cross-react with other anti-TNF agents or with biosimilars, and to compare the TNF-neutralizing capabilities of available anti-TNF options.

TNF neutralization was measured using a quantitative TNF sensor assay that consisted of HeLa 8D8 cells that express Green Flourescent Protein (GFP) under the control of a NF-кB response element.

All available anti-TNF therapies and the infliximab biosimilar CT-P13 (Inflectra, Remsima) were tested, and patient sera with anti-infliximab antibodies were tested for their potential to block activity of reference infliximab, the infliximab (F)ab2-fragment, CT-P13, and adalimumab. The sera were derived from a retrospective cohort of 23 patients treated with reference infliximab who had developed ADAs and consented to have their samples banked.

Infliximab, adalimumab, certolizumab, etanercept, and golimumab were tested at 0, 5, 10, 20, 40, and 100 ng/mL in the presence of 1 ng/ml of TNF. All the agents dose-dependently reduced the number of TNF-induced GFP-positive HeLa 8D8cells.

The second-generation agents, etanercept, certolizumab, and golimumab, demonstrated a stronger neutralizing effect toward TNF versus first-generation anti-TNF agents, infliximab and adalimumab. There was no statistically significant difference in the neutralizing effect reference versus biosimilar infliximab, however.

Serum samples of 2 ADA-positive patients with inflammatory bowel disease and samples from 2 ADA-positive patients with rheumatoid arthritis were used to evaluate the cross-reactivity between antibodies to adalimumab and infliximab. The sera with ADAs inhibited the effect of the infliximab F(ab)2-fragment, but did not block the TNF-neutralizing effect of adalimumab. This result, say the authors, means that it is likely that the anti-infliximab antibodies are directed against the F(ab)2-fragment, but no antigenic cross-reactivity was found between infliximab and adalimumab. In contrast, anti-infliximab antibodies blocked the TNF-neutralizing capacity of both reference and biosimilar infliximab, demonstrating that the 2 products have the same immunogenic epitopes.

The authors concluded that second-generation anti-TNF drugs show greater TNF-neutralizing properties, and furthermore, “In this study we show that there is no difference in either the [anti-TNF] effect or antigenicity of [reference infliximab] and its biosimilar CT-P13 (Inflectra) in vitro,” write the authors. The ADAs’ effect “…seems to be directed against the F(ab)2-fragment of the antibody and since an antibody reaction is very specific this proves similarity,” they wrote.

Reference

Buurman DJ, Blokzijl T, Festen EAM, et al. Quantitative comparison of the neutralizing capacity, immunogenicity and cross-reactivity of anti-TNF-α biologicals and an infliximab-biosimilar [published online December 11, 2018]. Plos One. doi: 10.1371/journal.pone.0208922.