Omalizumab in children.
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ABSTRACT:
SUBMITTER: Licari A
PROVIDER: S-EPMC4250568 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A considerable proportion of patients with H1-antihistamine-resistant chronic spontaneous urticaria (CSU) fails to respond to omalizumab. However, there is yet no available biomarker that accurately predicts such a response outcome. The utility of blood basophil and eosinophil levels and exosomal and basophil micro(mi)RNAs as biomarkers of response to omalizumab in CSU was explored. In this prospective cohort study of twenty patients with antihistamine-resistant CSU, subjects were treated with 3-monthly doses of omalizumab, and their response assessed using the weekly urticaria activity score (UAS7) for a period of 12-weeks. Basophil and eosinophil levels in the blood and differentially expressed exosomal and basophil miRNAs of complete responders compared to non-responders were identified at baseline. Canonical pathways, altered by differentially expressed miRNAs, were identified using Ingenuity Pathway Analysis (IPA). Complete responders had higher baseline basophil levels (≥21 cells/L) in the peripheral blood compared to non-responders (P = 0.005). Baseline levels of eosinophils did not differ between the study groups. Complete responders in comparison to non-responders had an expression profile characterized by a significantly higher expression of six exosomal miRNAs (miR-6499-5p, miR-7848, miR-4494-3p, miR-450a-2-3p, miR-6877-3p, and miR-3976) and lower expression of miR-141-3p. Complete responders also had higher expression of three basophil miRNAs (miR-1200, miR-1236-3p, and miR-4496). The exosomal miRNA expression profile was predicted by IPA to alter Tec Kinase Signaling pathway activity (P = 0.003).
2021-11-16 | GSE153579 | GEO
Project description:BackgroundResearch has underscored the effects of exposure and sensitization to allergens on the severity of asthma in inner-city children. It has also revealed the limitations of environmental remediation and guidelines-based therapy in achieving greater disease control.MethodsWe enrolled inner-city children, adolescents, and young adults with persistent asthma in a randomized, double-blind, placebo-controlled, parallel-group trial at multiple centers to assess the effectiveness of omalizumab, as compared with placebo, when added to guidelines-based therapy. The trial was conducted for 60 weeks, and the primary outcome was symptoms of asthma.ResultsAmong 419 participants who underwent randomization (at which point 73% had moderate or severe disease), omalizumab as compared with placebo significantly reduced the number of days with asthma symptoms, from 1.96 to 1.48 days per 2-week interval, a 24.5% decrease (P<0.001). Similarly, omalizumab significantly reduced the proportion of participants who had one or more exacerbations from 48.8 to 30.3% (P<0.001). Improvements occurred with omalizumab despite reductions in the use of inhaled glucocorticoids and long-acting beta-agonists.ConclusionsWhen added to a regimen of guidelines-based therapy for inner-city children, adolescents, and young adults, omalizumab further improved asthma control, nearly eliminated seasonal peaks in exacerbations, and reduced the need for other medications to control asthma. (Funded by the National Institute of Allergy and Infectious Diseases and Novartis; ClinicalTrials.gov number, NCT00377572.).
| S-EPMC3093964 | biostudies-literature
Project description:BackgroundTreatment regimens for omalizumab are guided by a dosing table that is based on total serum IgE and body weight. Limited data exist about onset and offset of omalizumab efficacy in children and adolescents or subgroups that most benefit from treatment.ObjectivesPost hoc analyses were conducted to (1) examine patient characteristics of those eligible and ineligible for omalizumab, (2) describe onset of effect after initiation of omalizumab and offset of treatment effect after stopping therapy, and (3) determine whether the efficacy differs by age, asthma severity, dosing regimen, and prespecified biomarkers.MethodsInner-city children and adolescents with persistent allergic asthma were enrolled in the Inner-City Anti-IgE Therapy for Asthma trial that compared omalizumab with placebo added to guidelines-based therapy for 60 weeks.ResultsTwo hundred ninety-three of 889 participants (33%) clinically suitable for omalizumab were ineligible for dosing according to a modified dosing table specifying IgE level and body weight criteria. Baseline symptoms were comparable among those eligible and ineligible to receive omalizumab, but other characteristics (rate of health care utilization and skin test results) differed. The time of onset of omalizumab effect was <30 days and time of offset was between 30 and 120 days. No difference in efficacy was noted by age or asthma severity, but high exhaled nitric oxide, blood eosinophils, and body mass index predicted efficacy.ConclusionsA significant portion of children and adolescents particularly suited for omalizumab because of asthma severity status may be ineligible due to IgE >1300 IU/mL. Omalizumab reduced asthma symptoms and exacerbations rapidly; features associated with efficacy can be identified to guide patient selection.
| S-EPMC4254887 | biostudies-literature
Project description:Childhood asthma is one condition within a family of allergic diseases, which includes allergic rhinitis, atopic dermatitis, and food allergy, among others. Omalizumab is an anti-IgE antibody therapy that was approved in Japan for children with asthma and added to the Japanese pediatric asthma guidelines in 2017. This review highlights the Japanese clinical perspectives in pediatric allergic asthma, and consideration for allergic comorbidities, and reflects on omalizumab clinical trials in progress to present comprehensive future opportunities.
| S-EPMC6365659 | biostudies-literature
Project description:Omalizumab is a widely used therapeutic anti-IgE antibody. Here we report the crystal structure of the omalizumab-Fab in complex with an IgE-Fc fragment. This structure reveals the mechanism of omalizumab-mediated inhibition of IgE interactions with both high- and low-affinity IgE receptors, and explains why omalizumab selectively binds free IgE. The structure of the complex also provides mechanistic insight into a class of disruptive IgE inhibitors that accelerate the dissociation of the high-affinity IgE receptor from IgE. We use this structural data to generate a mutant IgE-Fc fragment that is resistant to omalizumab binding. Treatment with this omalizumab-resistant IgE-Fc fragment, in combination with omalizumab, promotes the exchange of cell-bound full-length IgE with omalizumab-resistant IgE-Fc fragments on human basophils. This combination treatment also blocks basophil activation more efficiently than either agent alone, providing a novel approach to probe regulatory mechanisms underlying IgE hypersensitivity with implications for therapeutic interventions.
| S-EPMC4873975 | biostudies-literature
Project description:Severe refractory atopic dermatitis (AD) is a chronic, debilitating condition that is associated with elevated serum immunoglobulin E (IgE) levels. Thymic stromal lymphopoietin (TSLP), thymus and activation-regulated chemokine (TARC) and OX40 ligand (OX40L) are important immunologic factors involved in the pathogenesis of AD. Omalizumab, an anti-IgE antibody indicated for use in allergic asthma, is implicated in regulating allergen presentation by dendritic cells and the T cell response during the effector phases of allergic disease. We investigated if anti-IgE therapy modulates the allergen-specific responses mediated by the TSLP pathway in young patients with severe refractory AD.This was a randomized, double-blind, placebo-controlled study of 8 patients between the ages of 4 and 22 years (mean = 11.6 years) with severe refractory AD (clinical trials.gov NCT01678092). Serum IgE ranged from 218 to 1,890 (mean = 1,068 IU/ml). Subjects received omalizumab (n = 4) or placebo (n = 4) every 2-4 weeks over 24 weeks using a regimen extrapolated from the package insert. TSLP, TARC, OX40L and other cytokines involved in AD were measured by using cytometric bead arrays.All patients receiving omalizumab had strikingly decreased levels of TSLP, OX40L, TARC (involved in Th2 polarization) and interleukin (IL)-9 compared to placebo. In addition, there was a marked increase in IL-10, a tolerogenic cytokine, in the omalizumab-treated group. Patients on anti-IgE therapy had an improvement in clinical outcomes as measured by the SCORAD system; however, these effects were comparable to improvements in the control group.Anti-IgE therapy with omalizumab decreases levels of cytokines that are involved in Th2 polarization and allergic inflammation, including TSLP, TARC and OX40L.
| S-EPMC4161454 | biostudies-literature
Project description:Omalizumab is a humanized anti-IgE antibody that inhibits the binding of IgE to its receptors on mast cells and basophils, thus blocking the IgE-mediated release of inflammatory mediators from these cells. Omalizumab binds to the Fc domains of IgE in proximity to the binding site of the high-affinity IgE receptor FcℇRI, but the epitope and the mechanisms and conformations governing the recognition remain unknown. In order to elucidate the molecular mechanism of its anti-IgE activity, the aim was to analyse the interaction of omalizumab with human IgE. Therefore, IgE Fc Cℇ2-4 was recombinantly produced in mammalian HEK-293 cells. Functionality of the IgE Fc was proven by ELISA and mediator-release assays. Omalizumab IgG was cleaved with papain and the resulting Fab was purified by ion-exchange chromatography. The complex of IgE Fc with omalizumab was prepared by size-exclusion chromatography. However, crystals containing the complex were not obtained, suggesting that the process of crystallization favoured the dissociation of the two proteins. Instead, two structures of the omalizumab Fab with maximum resolutions of 1.9 and 3.0 Å were obtained. The structures reveal the arrangement of the CDRs and the position of omalizumab residues known from prior functional studies to be involved in IgE binding. Thus, the structure of omalizumab provides the structural basis for understanding the function of omalizumab, allows optimization of the procedure for complex crystallization and poses questions about the conformational requirements for anti-IgE activity.
| S-EPMC4388177 | biostudies-literature
Project description:Omalizumab is licensed as add-on therapy for patients with severe allergic asthma. Response is in most studies scored by the physician's global evaluation of treatment effectiveness (GETE). A good clinical and validated parameter for treatment response is currently missing. Also, there are no established criteria for identifying patients who will respond to omalizumab based on pre-treatment characteristics. The Dutch National Omalizumab in Asthma Registry was developed in 2011 to better evaluate inclusion criteria and measure treatment response after 4 months.This is a "real world" prospectively designed, observational data registry in which the outcomes of patients who received omalizumab between 2012 and 2015 were evaluated. Data were collected from all centers in the Netherlands comprising demographic features, criteria for starting treatment, GETE, FEV1, oral corticosteroid use and ACQ.65.5% of the 403 patients had a good or excellent response to omalizumab after 16 weeks according to the treating physician GETE. 64.5% fulfilled all the criteria for prescribing omalizumab at baseline. The mean ACQ improved from 2.96 at baseline to 1.83 at 16 weeks (p < 0.001). 75.3% of the responders showed more than 0.5 points improvement in the ACQ. The mean FEV1 increased from 71.58 to 79.06 (p < 0.001). There was no relationship between patients with a FEV1 <80 and ≥80% at baseline and response (p = 0.981). Most of the responders had a considerable improvement of FEV1 either/or ACQ or OCS use (88.3%). While 86.7% of the responders had an improvement of either ACQ or FEV1. 75.4% of the responders had an improvement of ACQ, while 50.4% had an improvement of FEV1. Finally 11.7% of the patients with no improvement of FEV1, ACQ or OCS use were considered to have a good response.This registry of 403 inadequately controlled severe allergic asthma patients in the Netherlands showed a good or excellent response of 65.5% to omalizumab after 16 weeks, in accordance with previous studies. The assumption that careful registration would lead to higher response rates could not be supported by the data from this registry. Improvement of ACQ appears to be a useful additional assessment tool to measure response in omalizumab treated patients.
| S-EPMC5530516 | biostudies-other
Project description:BackgroundOmalizumab is a humanized monoclonal anti-immunoglobulin E antibody, approved for the treatment of spontaneous chronic urticaria, with high efficacy and an excellent safety profile. Although its adverse effects are rare, allergic reactions and cardiovascular events were previously described.Case summaryThe authors describe the case of a 75-year-old woman, followed at the outpatient dermatology clinic due to spontaneous chronic urticaria, treated with omalizumab 300 mg every 4 weeks. After the 11th administration of omalizumab, the patient developed an episode of thoracalgia associated with electro- and echocardiographic abnormalities. Coronary angiogram excluded coronary artery disease, and left ventriculography demonstrated mid-apical akinesia and basal hyperkinesia, consistent with the Takotsubo syndrome (TS).DiscussionTakotsubo syndrome was already reported in association with other monoclonal antibodies. However, to our knowledge, this is the first case of TS following the administration of omalizumab.
| S-EPMC6439385 | biostudies-literature