BACKGROUND: Monoclonal antibodies directed at IgE demonstrate clinical efficacy in subjects with peanut allergy, but previous studies have not addressed the kinetics of the clinical response or the role of mast cells and basophils in the food-induced allergic response. OBJECTIVE: We sought to determine the kinetics of the clinical response to omalizumab and whether clinical improvement is associated with either mast cell or basophil suppression. METHODS: Subjects with peanut allergy were treated with omalizumab for 6 months and assessed for clinical and cellular responses. At baseline, subjects had a double-blind, placebo-controlled oral food challenge (OFC), skin prick test titration (SPTT), and basophil histamine release (BHR) to peanut. BHR was repeated at week 2 and then weekly until it decreased to less than 20% of baseline values. The OFCs and SPTTs were repeated after the BHR reduction (or at week 8 if BHR did not decrease) and again at 6 months. RESULTS: Fourteen subjects enrolled in the study. At the second food challenge, there was a significant increase in the threshold dose of peanut inducing allergic symptoms (80 to 6500 mg, P < .01). Peanut-induced BHR was either completely suppressed (n = 5) or 10-fold more allergen was required to induce maximal BHR (n = 9), and SPTT responses were not significantly changed from baseline. After 6 months of omalizumab, further changes in the OFC threshold dose or BHR were not observed, but a significant suppression in SPTTs was identified. CONCLUSIONS: The clinical response to omalizumab occurs early in treatment when the basophil, but not the mast cell, is suppressed, supporting a role for the basophil in acute food reactions.
"The use of IgE immunomodulatory therapies, including monoclonal antibodies and small molecules, has been under investigation in food allergies and has been reviewed recently in the literature [37-45]. Specifically, omalizumab has been shown to increase the threshold for adverse reactions on food challenge by up to 80 fold . After obtaining pharmacodynamic data using basophil assays and free IgE measurements in subjects with food allergies who received standard omalizumab dosing, we found that 8 weeks post standard omalizumab therapy is an optimal time to start oral immunotherapy [46,47]. "
[Show abstract][Hide abstract] ABSTRACT: Up to 30% of patients with food allergies have clinical reactivity to more than one food allergen. Although there is currently no cure, oral immunotherapy (OIT) is under investigation. Pilot data have shown that omalizumab may hasten the ability to tolerate over 4 g of food allergen protein.
To evaluate the safety and dose tolerability of a Phase 1 Single Site OIT protocol using omalizumab to allow for a faster and safe desensitization to multiple foods simultaneously.
Participants with multiple food allergies received OIT for up to 5 allergens simultaneously with omalizumab (rush mOIT). Omalizumab was administered for 8 weeks prior to and 8 weeks following the initiation of a rush mOIT schedule. Home reactions were recorded with diaries.
Twenty-five (25) participants were enrolled in the protocol (median age 7 years). For each included food, participants had failed an initial double-blind placebo-controlled food challenge at a protein dose of 100 mg or less. After pre-treatment with omalizumab, 19 participants tolerated all 6 steps of the initial escalation day (up to 1250 mg of combined food proteins), requiring minimal or no rescue therapy. The remaining 6 were started on their highest tolerated dose as their initial daily home doses. Participants reported 401 reactions per 7,530 home doses (5.3%) with a median of 3.2 reactions per 100 doses. Ninety-four percent (94%) of reactions were mild. There was one severe reaction. Participants reached their maintenance dose of 4,000 mg protein per allergen at a median of 18 weeks.
These phase 1 data demonstrate that rush OIT to multiple foods with 16 weeks of treatment with omalizumab could allow for a fast desensitization in subjects with multiple food allergies. Phase 2 randomized controlled trials are needed to better define safety and efficacy parameters of multi OIT experimental treatments with and without omalizumab.
[Show abstract][Hide abstract] ABSTRACT: This review highlights some of the research advances in anaphylaxis; hypersensitivity reactions to foods, drugs, and insects; and allergic skin diseases that were reported in the Journal in 2011. Food allergy appears to be increasing in prevalence and carries a strong economic burden. Risk factors can include dietary ones, such as deficiency of vitamin D and timing of complementary foods, and genetic factors, such as filaggrin loss-of-function mutations. Novel mechanisms underlying food allergy include the role of invariant natural killer T cells and influences of dietary components, such as isoflavones. Among numerous preclinical and clinical treatment studies, promising observations include the efficacy of sublingual and oral immunotherapy, a Chinese herbal remedy showing promising in vitro results, the potential immunotherapeutic effects of having children ingest foods with baked-in milk if they tolerate it, and the use of anti-IgE with or without concomitant immunotherapy. Studies of allergic skin diseases, anaphylaxis, and hypersensitivity to drugs and insect venom are elucidating cellular mechanisms, improved diagnostics, and potential targets for future treatment. The role of skin barrier abnormalities, as well as the modulatory effects of the innate and adaptive immune responses, are major areas of investigation.
The Journal of allergy and clinical immunology 12/2012; 129(1):76-85. DOI:10.1016/j.jaci.2011.11.016 · 11.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: A recent study of subjects with peanut allergy treated with omalizumab generated some results that were concordant with a study of subjects with cat allergy treated with omalizumab. However, there were differences that provided additional insight into the nature of the cellular responses in allergic subjects. OBJECTIVE: We sought to determine the cause for failure to suppress the allergen-induced basophil response during treatment with omalizumab. METHODS: Patients with peanut allergy were treated with omalizumab. Clinical, serologic, and cellular indices relevant to the response of the subjects and their peripheral blood basophil values (specific/total IgE ratio, cell-surface FcεRI expression, and histamine release responses to anti-IgE antibody or peanut allergen) were obtained at 3 times. RESULTS: After treatment, approximately 60% of the subjects' basophil responses to peanut allergen did not significantly decrease. In 40% of cases, the in vitro basophil response to peanut allergen increased 2- to 7-fold. The increases were associated with 2 primary factors: a high (>10%) specific/total IgE ratio and an increase in the intrinsic response of the basophil to IgE-mediated stimulation. The extent to which the basophil response to peanut allergen increased was inversely correlated with improvement in the patient's ability to tolerate ingestion of peanut. CONCLUSION: The basophil response during treatment with omalizumab is a consequence of 2 competing factors: suppression of allergen-specific IgE on the cell surface versus increased intrinsic sensitivity to IgE-mediated stimulation. In subjects with peanut allergy, the basophil response appears to mitigate against the ability of omalizumab to improve the patient's tolerance of oral allergen.
The Journal of allergy and clinical immunology 07/2012; 130(5). DOI:10.1016/j.jaci.2012.05.038 · 11.48 Impact Factor
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