Intranasal administration of allergen increases specific IgE whereas intranasal omalizumab does not increase serum IgE levels-A pilot study

J Eckl-Dorna, R Fröschl, C Lupinek, R Kiss, P Gattinger, K Marth, R Campana, I Mittermann, K Blatt, P Valent, R Selb, A Mayer, K Gangl, I Steiner, J Gamper, T Perkmann, P Zieglmayer, P Gevaert, R Valenta, V Niederberger, J Eckl-Dorna, R Fröschl, C Lupinek, R Kiss, P Gattinger, K Marth, R Campana, I Mittermann, K Blatt, P Valent, R Selb, A Mayer, K Gangl, I Steiner, J Gamper, T Perkmann, P Zieglmayer, P Gevaert, R Valenta, V Niederberger

Abstract

Background: Administration of the therapeutic anti-IgE antibody omalizumab to patients induces strong increases in IgE antibody levels.

Objective: To investigate the effect of intranasal administration of major birch pollen allergen Bet v 1, omalizumab or placebo on the levels of total and allergen-specific IgE in patients with birch pollen allergy.

Methods: Based on the fact that intranasal allergen application induces rises of systemic allergen-specific IgE, we performed a double-blind placebo-controlled pilot trial in which birch pollen allergic subjects were challenged intranasally with omalizumab, placebo or birch pollen allergen Bet v 1. Total and allergen-specific IgE, IgG and basophil sensitivity were measured before and 8 weeks after challenge. For control purposes, total, allergen-specific IgE levels and omalizumab-IgE complexes as well as specific IgG levels were studied in subjects treated subcutaneously with either omalizumab or placebo. Effects of omalizumab on IgE production by IL-4/anti-CD40-treated PBMCs from allergic patients were studied in vitro.

Results: Intranasal challenge with Bet v 1 induced increases in Bet v 1-specific IgE levels by a median of 59.2%, and this change differed significantly from the other treatment groups (P = .016). No relevant change in allergen-specific and total IgE levels was observed in subjects challenged with omalizumab. Addition of omalizumab did not enhance IL-4/anti-CD40-induced IgE production in vitro. Significant rises in total IgE (mean IgE before: 131.83 kU/L to mean IgE after: 505.23 kU/L) and the presence of IgE-omalizumab complexes were observed after subcutaneous administration of omalizumab.

Conclusion: Intranasal administration of allergen induced rises of allergen-specific IgE levels, whereas intranasal administration of omalizumab did not enhance systemic total or allergen-specific IgE levels.

Keywords: IgE; allergen; half-life; intranasal challenge; omalizumab.

© 2017 The Authors. Allergy Published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Design of the intranasal challenge study. A, Subjects were challenged intranasally with either omalizumab, Bet v 1 or placebo on 3 consecutive days (d1‐d3, arrows, top). Blood samples (arrows, bottom) were taken before the first (t1) challenge and on days 21 (t2), 35 (t3) and 56 (t4) (±4 days) after the first challenge. B, Flow chart depicting number of subjects who were screened (n = 24), randomized (n = 15), and who completed (n = 14) the study
Figure 2
Figure 2
Percentage change in total and Bet v 1‐specific serum IgE levels following intranasal challenge with omalizumab, Bet v 1 or placebo. Percentage changes (y‐axes) of (A) Bet v 1‐specific and (B) total IgE levels between t1 (before challenge) and t3 (day 35 ± 4 days after challenge) are shown for each subject. Significant differences between the treatment groups were observed only for Bet v 1‐specific IgE (Kruskal‐Wallis test: P = .0053) levels but not for total IgE levels (Kruskal‐Wallis test: P = .0521). Pairwise comparisons using the two‐sided Wilcoxon rank‐sum test were therefore only performed for Bet v 1‐specific IgE levels and P values are indicated
Figure 3
Figure 3
Effects of changes of allergen‐specific IgE levels on basophil activation. (A) Rat basophilic leukaemia (RBL) cells expressing human FcεRI were loaded with sera obtained at t1 and t3 and then stimulated with Bet v 1. Percentage changes (y‐axes) of β‐hexosaminidase release between t3 and t1 are shown. (B) Peripheral mononuclear cells (PBMCs) from subjects challenged intranasally (x‐axis: omalizumab, Bet v 1 or placebo) were stimulated with Bet v 1. Differences in the stimulation indices for the upregulation of CD203c between t3 and t1 are shown as percentage changes (y‐axes). Significant differences between the 3 treatment groups were observed for the RBL assay (Kruskal‐Wallis test: P = .0463) shown in (A) but not for the assays using basophils directly collected from subjects (Kruskal‐Wallis test: P = .1934) shown in (B). Pairwise comparisons using the two‐sided Wilcoxon rank‐sum test were therefore only performed for the RBL assay and P‐values are indicated
Figure 4
Figure 4
Total serum IgE and IgE‐omalizumab complex levels in subjects after subcutaneous omalizumab administration. (A) Total serum IgE levels (y‐axis: kU/L) and (B) levels of IgE‐omalizumab complexes (y‐axis: μg/mL) in subjects before and after subcutaneous administration of omalizumab (left, n = 16) or placebo (right, n = 6). Sera “Before s.c. administration” were obtained at visit V1 (V1: screening visit, at least 2 weeks before visit V2 where first dose of omalizumab was administered) except for subject S9 where serum was obtained at V2. Sera “After s.c. administration” were obtained at visit V8 (12 weeks after first subcutaneous administration) except for subject S18 where serum obtained at visit V6 (8 weeks after first subcutaneous administration) and for subject S16 where serum was obtained at visit V10 (16 weeks after first subcutaneous administration). (C) Correlation of total IgE levels (x‐axis) with IgE‐omalizumab complexes (y‐axis) is displayed for patients after subcutaneous omalizumab administration. Significant results (P‐values) are indicated

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