Cellular Response to Infliximab May Be Linked With ADA Development

Like all biologics, infliximab has the potential for immunogenicity, and the development of antidrug antibodies (ADAs) can lead to loss of response or hypersensitivity reactions. A newly published paper sought to evaluate the development of a cellular response to infliximab and whether such a response could predict ADA development.
The Center for Biosimilars Staff
March 20, 2019
Like all biologics, infliximab has the potential for immunogenicity, and the development of antidrug antibodies (ADAs) can lead to loss of response or hypersensitivity reactions. A newly published paper sought to evaluate the development of a cellular response to infliximab and whether such a response could predict ADA development.

The study, published in Frontiers in Immunology, enrolled 17 patients with immune-mediated inflammatory disorders. Investigators collected blood samples at baseline and before each of 8 infusions of infliximab. Another 8 patients’ samples, comprising a control group, were assessed before and after a switch from reference infliximab to biosimilar CT-P13 to analyze response to infliximab peptides.

The investigators assessed the proliferative response of peripheral mononuclear cells (PBMCs) from 11 of the patients before treatment and before infusion 5. They found that the number of peptides recognized by T cells was higher after the fourth treatment than prior to treatment, and that peptide recognition was increased during treatment in 81.8% of patients, suggesting that the majority of patients were sensitized to infliximab. However, in the control group, the number of recognized peptides was unchanged in PBMCs before and after the switch to a biosimilar.

The investigators had found in a prior study that infliximab expands a proportion of memory T cells that produce the inflammatory cytokine interleukein (IL)-10, and in this study, they evaluated its production with a focus on regulatory activity to adaptive cytokines.

Analyzing the kinetics of IL-10 messenger RNA (mRNA) to infliximab-cultured PBMCs, they found that IL-10 mRNA increased from the first treatment to the eighth treatment in 88.2% of patients. While PBMCs from ADA-negative patients expressed IL-10 mRNA at all time points, 3 of the 5 patients who developed ADAs showed IL-10 mRNA.

The mean values of IL-10 mRNA expression detected at different time points were higher in ADA-negative patients than in ADA-positive patients, while interferon-gamma (IFN-γ) values were higher (though not significantly so) in ADA-positive patients than in ADA-negative patients.

The IL-10/IFN-γ ratio of mRNA values was significantly lower in ADA-positive patients than in ADA-negative patients at treatments 1 and 2 (P = .044 and P = .01, respectively).

The IL10/IFN-γ ratio was also higher in patients with good clinical response than in patients with poor clinical outcomes. 

“Even though the limitation of this study lies in the very small number of patients, mainly in those testing [ADA-positive], it suggests a predictive role of low levels of IL-10 on the development of [ADAs],” write the authors, adding that, overall, the study suggests that ADA development following a cellular adaptive response to infliximab is likely associated with the balance between IL-10 and IFN-γ cytokines.

Reference
Pratesi S, Nencini F, Grosso F, et al. T cell response to infliximab in exposed patients: a longitudinal analysis [published online January 11, 2019]. Front Immunol. doi: 10.3389/fimmu.2018.03113.

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