Interferon α kinoid induces neutralizing anti-interferon α antibodies that decrease the expression of interferon-induced and B cell activation associated transcripts: analysis of extended follow-up data from the interferon α kinoid phase I/II study

Julie Ducreux, Frédéric A Houssiau, Pierre Vandepapelière, Christian Jorgensen, Estibaliz Lazaro, François Spertini, Fabien Colaone, Camille Roucairol, Marion Laborie, Thérèse Croughs, Géraldine Grouard-Vogel, Bernard R Lauwerys, Julie Ducreux, Frédéric A Houssiau, Pierre Vandepapelière, Christian Jorgensen, Estibaliz Lazaro, François Spertini, Fabien Colaone, Camille Roucairol, Marion Laborie, Thérèse Croughs, Géraldine Grouard-Vogel, Bernard R Lauwerys

Abstract

Objective: IFN α Kinoid (IFN-K) is a therapeutic vaccine composed of IFNα2b coupled to a carrier protein. In a phase I/II placebo-controlled trial, we observed that IFN-K significantly decreases the IFN gene signature in whole blood RNA samples from SLE patients. Here, we analysed extended follow-up data from IFN-K-treated patients, in order to evaluate persistence of neutralizing anti-IFNα Abs antibodies (Abs), and gene expression profiling.

Methods: Serum and whole blood RNA samples were obtained in IFN-K-treated patients included in the follow-up study, in order to determine binding and neutralizing anti-IFNα Ab titres, and perform high-throughput transcriptomic studies.

Results: Neutralization studies of 13 IFNα subtypes demonstrated the polyclonal nature of the Ab response induced by IFN-K. Follow-up analyses in six patients confirmed a significant correlation between neutralizing anti-IFNα Ab titres and decrease in IFN scores compared to baseline. These analyses also revealed an inhibitory effect of IFNα blockade on the expression of B cell associated transcripts.

Conclusions: IFN-K induces a polyclonal anti-IFNα response that decreases IFN- and B cell-associated transcripts.

Trial registration: ClinicalTrials.gov, clinicaltrials.gov, NCT01058343.

Keywords: B cells; interferon alpha; interferon alpha kinoid; interferon signature; systemic lupus erythematosus.

© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology.

Figures

Fig. 1
Fig. 1
Effects of neutralizing anti-IFNα Abs on the expression of IFN-induced genes (A) Mean-centred, log2-transformed normalized expression of 21 IFN-induced probe sets (green square = −2.5; red square = +2.5) used to calculate IFN scores (probe set identifications are displayed in supplementary Table S7), IFN scores and serum anti-IFNα Ab titres (U/ml) in 10 controls and 6 IFN-K−treated SLE patients are displayed at the indicated time points, at which transcriptomic, biological and serological data were available. (B) Correlation between log10-transformed serum neutralizing anti-IFNα Abs and changes in IFN scores compared with baseline or (C) changes in serum C3 compared with baseline. (D) Evolution of serum dsDNA Ab titres at the same time points. Spearman ρ correlation coefficients are displayed on the graphs. Patients’ study numbers: filled square = 030501; open circle = 030402; filled circle = 060102; filled rhombus = 010101; filled inverted triangle = 030401; filled triangle = 060101.
Fig. 2
Fig. 2
Genes downregulated by IFN-K are significantly enriched in B cell–associated transcripts Serum neutralizing anti-IFNα Ab titres display a strong (−0.9 A) Radar plot showing the relative expression of these 156 transcripts in the indicated experimental conditions. The B cell score is calculated using the 10 most differentially expressed genes in proliferating CpG-stimulated B cells. (B) Correlation between log10-transformed serum neutralizing anti-IFNα Abs and changes in B cell scores compared with baseline. Patients’ study numbers: filled square = 030501; open circle = 30402; filled circle = 060102; filled rhombus = 010101; filled inverted triangle = 030401; filled triangle = 060101. (C) Box plots (median, interquartile range, 10th and 90th percentiles) showing the changes from day 0 in the expression of the 10 probe sets used in the B cell score in all patients included in the phase I/II trial. The differences in the average log2 expression of each of these probe sets between the indicated day and day 0 were calculated for patients treated with placebo (n = 7), IFN signature−negative (n = 7) and IFN signature−positive (n = 12) patients treated with IFN-K. *P < 0.05 using the Kruskal−Wallis tests.

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Source: PubMed

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