Extracorporeal IgE Immunoadsorption in Allergic Asthma: Safety and Efficacy

Abstract

Background: Prevention of IgE-binding to cellular IgE-receptors by anti-IgE (Omalizumab) is clinically effective in allergic asthma, but limited by IgE threshold-levels. To overcome this limitation, we developed a single-use IgE immunoadsorber column (IgEnio). IgEnio is based on a recombinant, IgE-specific antibody fragment and can be used for the specific extracorporeal desorption of IgE.

Objective: To study safety and efficacy of IgEnio regarding the selective depletion of IgE in a randomized, open-label, controlled pilot trial in patients with allergic asthma and to investigate if IgEnio can bind IgE-Omalizumab immune complexes.

Methods: Fifteen subjects were enrolled and randomly assigned to the treatment group (n=10) or to the control group (n=5). Immunoadsorption was done by veno-venous approach, processing the twofold calculated plasma volume during each treatment. A minimum average IgE-depletion of 50% after the last cycle in the intention-to-treat population was defined as primary endpoint. Safety of the treatment was studied as secondary endpoint. In addition, possible changes in allergen-specific sensitivity were investigated, as well as clinical effects by peak flow measurement and symptom-recording. The depletion of IgE-Omalizumab immune complexes was studied in vitro. The study was registered at clinicaltrials.gov (NCT02096237) and conducted from December 2013 to July 2014.

Results: IgE immunoadsorption with IgEnio selectively depleted 86.2% (±5.1% SD) of IgE until the end of the last cycle (p<0.0001). Removal of pollen allergen-specific IgE was associated with a reduction of allergen-specific basophil-sensitivity and prevented increases of allergen-specific skin-sensitivity and clinical symptoms during pollen seasons. IgEnio also depleted IgE-Omalizumab immune complexes in vitro. The therapy under investigation was safe and well-tolerated. During a total of 81 aphereses, 2 severe adverse events (SAE) were recorded, one of which, an episode of acute dyspnea, possibly was related to the treatment and resolved after administration of antihistamines and corticosteroids.

Conclusions: This pilot study indicates that IgE immunoadsorption with IgEnio may be used to treat patients with pollen-induced allergic asthma. Furthermore, the treatment could render allergic patients with highly elevated IgE-levels eligible for the administration of Omalizumab and facilitate the desorption of IgE-Omalizumab complexes. This study was funded by Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany.

Keywords: Allergy; Asthma; IgE; IgEnio; Immunoadsorption.

Graphical abstract

Fig. 1

Enrollment, randomization and study design. (a) After screening (yellow; AV1, CV1 in b), subjects were allocated to the apheresis (blue) or the control group (pink). (b) Treatment-visits (AV2, AV3, etc.) are indicated by blue boxes, corresponding visits of the control group (CV2, CV3, etc.) by pink boxes. Intervals between treatment weeks, including control visits (AV5, CV4, etc.) are shown in white. The study was completed after a follow-up visit in week 16 (orange; AV14 and CV11). Weeks after randomization are shown at the bottom. pt./pts. – patient/s; IC – informed consent; AV – visit apheresis group; CV – visit control group.

Fig. 2

Relative IgE-depletion and absolute IgE-levels. (a) Mean (± SD) depletion rates (y-axes: % IgE-reduction) of total IgE (top chart), IgE to seasonal (center) and perennial allergen sources (bottom) are shown for each treatment visit (x-axes) of the apheresis group. (b) Absolute total IgE-levels (y-axis: U/ml) are shown as box-and-whisker plots for the screening visit, the first (Start) and the last visit (End) of each treatment cycle, for control- and follow-up visits (x-axis). Blue boxes show results for the treatment, red boxes for the control group, outliers are indicated by circles. The dashed line corresponds to median total IgE-levels for both groups at the screening visit. Significant differences between start and end of the respective cycle are indicated (**p ≤ 0.01).

Fig. 3

Isotype specificity of IgEnio. Relative changes (y-axis: % changes to pre-treatment values) in serum IgM (gray), IgG (green), IgA (orange) and albumin (purple) are shown for each treatment cycle (x-axis) for the apheresis group. Error bars represent mean relative changes ± standard deviations. Significant differences to changes in serum albumin are indicated (**p ≤ 0.01).

Fig. 4

Changes in allergen-specific skin- and basophil-reactivity and in sIgE-levels. Relative changes (y-axes: fold changes) of (a) total wheal-areas from skin prick testing (SPT) and (b) of basophil-sensitivity (CD203c BAT – basophil activation test measuring CD203c upregulation; AUC – area under the curve) are shown as scatter plots for control and follow-up visits (x-axes) for birch (left) and grass pollen allergens (right). Results from individual subjects are colour-coded and displayed for the apheresis (filled circles) and for the control group (open boxes) with the respective median levels indicated by horizontal black lines for each group and visit. (c) Relative changes of sIgE-levels to birch (left) and grass (right) are displayed for the same subjects from (a) and (b) (top-charts: apheresis group, bottom-charts: control group). Weeks of study duration are shown underneath the x-axes with birch- and grass seasons highlighted by yellow boxes and treatment weeks in purple. Dashed horizontal lines indicate baseline levels. AV – visit apheresis group; CV – visit control group.

Fig. 5

Changes in peak flow and symptom scores. (a) Peak flow results (y-axis: l/s), (b) overall severity of allergy-related symptoms (y-axis: VAS – visual analogue scale) and (c) severity of lung symptoms (y-axis: lung symptom score), based on daily assessment by the patients, are shown for the complete study period (x-axes: days from treatment start). Blue curves represent results from the apheresis group and red curves from the control group. Error bars show mean values, ± SD. Treatment weeks are highlighted by purple boxes, birch and grass pollen seasons by yellow boxes.

Fig. 6

In vitro IgE-depletion from serum samples after addition of Omalizumab. Two serum samples with total IgE-levels < 300 U/ml (a, low IgE) or > 1400 U/ml (b, high IgE), without (yellow bars) and with different IgE-to-Omalizumab ratios (x-axes: 1:1 – pink bars; 1:40 – brown bars) were applied to IgEnio adsorber material. Relative depletion rates of total-IgE are shown (y-axes).