Omalizumab efficacy in cases of chronic spontaneous urticaria is not explained by the inhibition of sera activity in effector cells

Eva Serrano-Candelas,Jaime Algorta,Marta Ferrer,Olga Vega,Joan Bartra,Jorge M Núñez-Córdoba,Gabriel Gastaminza,Maria Teresa Audicana,Margarita Martin,Antonio Valero,Rubén Martínez-Aranguren

doi:10.1038/s41598-017-09361-4

Abstract

Omalizumab (OmAb) is a humanized anti-IgE antibody approved for the treatment of chronic spontaneous urticaria (CSU). OmAb’s mechanism of action is known to include actions on free IgE and on pre-bound IgE. However, OmAb is equally and rapidly effective against autoimmune and non-autoimmune urticaria where IgE involvement is not clear, suggesting the involvement of additional mechanisms of action. In this study, we sought to investigate the ability of OmAb to inhibit mast cell and basophil degranulation induced by sera from CSU patients. For this purpose, we performed a comparison between the in vitro incubation of sera from CSU patients treated with OmAb and the in vivo administration of OmAb in a clinical trial. We found that OmAb added in vitro to sera from CSU patients did not modify the ability of the sera to induce cell degranulation. Similarly, the sera from patients treated with OmAb in the context of the clinical trial who had a good clinical outcome maintained the capacity to activate mast cells and basophils. Thus, we conclude that the beneficial activity of OmAb does not correlate with the ability of patient sera to induce cell degranulation.

Highlights

Omalizumab (OmAb) is a biological drug that recognizes IgE at the same epitope where IgE is bound to its high-affinity receptor, FcεRI
In an attempt to better understand the mechanisms of action of OmAb in chronic spontaneous urticaria (CSU) and, more importantly, to better understand the pathophysiology of this disease, we studied the influence of OmAb on the ability of CSU sera to activate mast cells and basophils
We determined whether the ability of sera from CSU patients to activate mast cells and primary basophils is altered after OmAb treatment in the context of a clinical trial

Summary

Introduction

Omalizumab (OmAb) is a biological drug that recognizes IgE at the same epitope where IgE is bound to its high-affinity receptor, FcεRI. Our recent data suggest that this occurs in mast cells and confirm previous basophil data at physiological dose ranges (30–100 μg/ ml, 0.2–0.67 μM) in a time- and dose-dependent manner[3] In these conditions, OmAb was able to inhibit early IgE-triggered events, such as phosphorylation of PLCγ, LAT and Syk, as well as phosphorylation of ERK and later events, such as upregulation of CD63 and leukotriene synthesis[3]. It is widely accepted that CSU has an autoimmune component[8], wherein dermal mast cells and basophils in CSU patients are triggered by circulating IgE against autoantigens[9], by IgG against FcεRI10, 11 or by IgG against IgE itself[12], which would be present in the sera of CSU patients. We evaluated whether the levels of histamine, tryptase and C-reactive protein in sera from CSU patients change during treatment to evaluate their use as potential markers for the efficacy of OmAb treatment

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