Basic and clinical immunology
Combination treatment with omalizumab and rush immunotherapy for ragweed-induced allergic rhinitis: Inhibition of IgE-facilitated allergen binding

https://doi.org/10.1016/j.jaci.2007.05.034Get rights and content

Background

The combination of anti-IgE (omalizumab) therapy with ragweed injection immunotherapy for seasonal allergic rhinitis results in a significant reduction in systemic side effects and enhanced efficacy compared with immunotherapy alone. One proposed mechanism of immunotherapy is to induce regulatory antibodies that inhibit facilitated antigen presentation.

Objectives

We sought to determine whether the combination protocol has a cumulative effect on inhibition of facilitated antigen presentation both during and after discontinuation of treatment.

Methods

Ragweed allergen immunotherapy with and without omalizumab therapy was tested in a 4-arm, double-blind, placebo-controlled study. Flow cytometry was used to detect serum inhibitory activity for IgE-facilitated CD23-dependent allergen binding to B cells as a surrogate marker for facilitated antigen presentation. Serum ragweed-specific IgG4 was measured by means of ELISA.

Results

Immunotherapy alone resulted in partial inhibition of allergen-IgE binding after 5 to 19 weeks of treatment compared with baseline (P < .01). Complete inhibition of allergen-specific IgE binding was observed in both treatment groups receiving omalizumab (P < .001). Allergen-specific IgG4 levels were only increased after immunotherapy (P < .05), both in the presence and absence of anti-IgE treatment. Combined treatment resulted in the induction of long-lasting inhibitory antibody function for up to 42 weeks compared with either treatment alone.

Conclusion

Ragweed immunotherapy induced serum regulatory antibodies that partially blocked binding of allergen-IgE complexes to B cells. Additional treatment with anti-IgE, by directly blocking IgE binding to CD23, completely inhibited allergen-IgE binding.

Clinical implications

The combination of ragweed immunotherapy and anti-IgE resulted in prolonged inhibition of allergen-IgE binding compared with either treatment alone, events that might contribute to enhanced efficacy.

Section snippets

Patients

Patients (21-51 years of age) with a minimum 2-year history of ragweed-induced allergic rhinitis and no recent immunotherapy were selected (Table I). Subject groups showed similar baseline characteristics, except for total IgE, which was lower in the omalizumab-only group compared with the immunotherapy-only group (P < .05). Patients were required to have a positive skin prick test result to short ragweed extract (ALK-Abelló, Round Rock, Tex), as defined by a wheal 3 mm greater in diameter than

Characterization of the ragweed-FAB assay

Initial experiments were aimed to validate the FAB assay (Fig 1) in the context of ragweed allergy. We identified sera from subjects with ragweed allergy containing high ragweed-specific IgE levels that could facilitate binding of allergen to CD23+ (FcɛRII) EBV-transformed B cells. Fig 2, A, shows that binding occurs in an allergen-dependent manner, and optimal binding occurs between 1 and 3 μg/mL. We next investigated the effect of diluting the ragweed-specific high-IgE “indicator” serum in

Discussion

Ragweed immunotherapy was associated with increases in allergen-specific IgG4 levels and increased serum inhibitory activity, as measured by the facilitated antigen binding assay. Treatment with omalizumab completely inhibited facilitated antigen binding but did not influence IgG4 levels. The inhibitory effects of omalizumab alone were observed for up to 30 weeks after discontinuation of treatment. Combination treatment with omalizumab and immunotherapy enhanced the serum inhibitory properties

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    Supported by the Immune Tolerance Network.

    Disclosure of potential conflict of interest: T. B. Casale has consultant arrangements with Genentech and Novartis; has received research support from Genentech and Novartis; and has served on the speakers' bureau for Genentech and Novartis. S. R. Durham has consultant arrangements with ALK-Abelló, GlaxoSmithKline, and Novartis; has received research support from ALK-Abelló, GlaxoSmithKline, and UCB Pharma; and has served on the speakers' bureau for ALK-Abelló and Allergy Therapeutics. The rest of the authors have declared that they have no conflict of interest.

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