Free IgE Levels Research Articles

Omalizumab-induced reductions in mast cell FcεRI expression and function

Background By design, omalizumab binds free IgE in the circulation and prevents its attachment to the surface of mast cells and basophils, thereby preventing them from responding to allergens. Previously, omalizumab rapidly reduced free IgE levels, as well as basophil high-affinity IgE receptors, leading to significant reductions in basophil mediator response to allergen. It is assumed that tissue mast cells are similarly altered in their FcεRI density and function. Objective We examined the phenotypic shift of skin mast cells in parallel to that of blood basophils in 3 subjects infused with omalizumab. Methods Three subjects with allergic rhinitis underwent intradermal skin test titration with house dust mite antigen at days 0, 7, 70, and 196 of omalizumab treatment. As control subjects, 5 untreated subjects with allergic rhinitis were evaluated at similar time points. All subjects underwent skin biopsy 18 to 24 hours later at the site of allergen injection. Biopsy specimens were characterized by means of immunohistochemisty for tryptase and FcεRIα immunoreactivity, as well other markers (CD3, CD45RO, CD68, cutaneous lymphocyte antigen, and major basic protein). Results Omalizumab recipients, but not control subjects, demonstrated reductions in FcεRIα immunoreactivity at days 70 and 196 in parallel with reductions in the acute wheal response to allergen. However, no reductions in tryptase-positive cells were noted at these time points. Conclusion Reductions in free IgE levels by omalizumab leads to a rapid reduction in basophil FcεRI receptor expression. In contrast, the time course for the decrease of FcεRI expression in skin mast cells is slower and associated with decreased acute allergen wheal size.

Seasonal variations of serum-IgE and potential impact on dose-calculation of omalizumab (rhuMab-E25, anti-IgE)

The anti-IgE antibody Omalizumab has been approved for the treatment of perennial allergic asthma. Dosing of omalizumab is adjusted according to total IgE levels and body weight, and a near complete suppression of free IgE is deemed to be necessary for optimal efficacy. Many asthmatics, however, have additional sensitisations against seasonal allergens, e. g. pollen, and seasonal exposure may increase total and specific IgE levels ("boost"), thus leading to an imbalance between IgE levels and omalizumab with possible impact on therapeutic outcome. We studied serum total and specific (timothy grass) IgE levels in 17 patients with seasonal allergic rhinitis and/or asthma prior to and during the grass pollen season. Based on total IgE levels, we then calculated hypothetical doses of omalizumab required for treatment at each time point. During the pollen season, total IgE increased significantly from a pre-seasonal mean of 89 (50 - 178) kU/l (geom. mean with 95 % confidence interval) to 126 (63 - 251) kU/l (p = 0.0006). Accordingly, specific IgE increased from 11 (6.3 - 19) kU/l to 15.1 (8.3 - 29) kU/l (p = 0.0013). Calculated doses of omalizumab based on pre-seasonal IgE levels were: no dosing (IgE < 30 kU/l): n = 2; 150 mg 4-weekly: n = 7; 300 mg 4-weekly: n = 2; 225 mg 2-weekly: n = 4; 300 mg 2-weekly: n = 1; 375 mg 2-weekly: n = 1. Based on seasonal IgE levels, doses of omalizumab would have changed in 5/17 patients requiring the next possible dosing step. Of these, two patients would have fallen out of the current dosing scheme. A seasonal increase of serum total and specific IgE can be observed in patients with pollen allergy, although this increase would have no impact on omalizumab doses in the majority of patient. Individual variations, however, can be large and necessitate a dose correction. Therefore, therapeutic monitoring of free IgE levels during anti-IgE treatment appears as desirable tool.

Etiopathogenesis and management of perennial allergic rhinitis: a state-of-the-art review.

Perennial allergic rhinitis is an inflammatory disorder characterized by symptoms of nasal congestion, rhinorrhea, sneezing, and itching. The prevalence of allergic rhinitis is quite common and affects 20% or more of various populations. Some patients with allergic rhinitis are symptomatic only during the pollen season, while many others are allergic to multiple allergens including indoor allergens such as house dust mites, animal dander, cockroaches, and fungi, which lead to perennial symptoms. Immunoglobulin (Ig)-E is the proximate cause of perennial allergic rhinitis. Circulating IgE antibodies bind to the high affinity IgE receptor on mast cells and basophils. IgE antibodies, bound to the receptors crosslinked by allergen, initiate the secretion of inflammatory mediators including histamine, leukotrienes, and cytokines. These mediators can induce both acute and chronic changes that result in symptoms of allergy. Many therapies are approved for the treatment of allergic rhinitis including intranasal corticosteroids, antihistamines with or without decongestants, and nasal cromolyn sodium (sodium cromoglicate). Allergen avoidance is the mainstay of therapy for many patients but is not always practical. For those patients who have not responded to appropriate medications, allergen specific immunotherapy may also be effective.A number of studies with omalizumab have shown that it is effective in the treatment of seasonal allergic rhinitis induced by pollen such as ragweed and birch pollen. Omalizumab is a molecularly cloned humanized monoclonal antibody inhibiting human IgE. It binds specifically to the region of the IgE molecule that binds to the IgE receptor on the mast cell or basophils. Because omalizumab cannot bind IgE molecules that are already bound to the surface receptors on mast cells and basophils, it does not stimulate secretion of mediators from these cells. Omalizumab does not appear to stimulate an immune response against itself. It rapidly reduces free serum IgE levels by over 95% when administered at therapeutic doses and also results in the reduction of IgE receptors on mast cells and basophils. The combined effects of reduction of both free IgE in serum and the receptor density on the mast cells or basophils results in decreased allergen-stimulated mediator release. Preliminary studies in the treatment of perennial allergic rhinitis supports omalizumab's efficacy and safety. The compound has been well tolerated. Aside from urticarial reactions, adverse effects appear to be minimal. Omalizumab is the first of several new immune-based specifically targeted molecules that may prove to be extremely valuable in the treatment of perennial allergic rhinitis, as it is often unresponsive to traditional therapies.

Pharmacodynamics of omalizumab: implications for optimised dosing strategies and clinical efficacy in the treatment of allergic asthma

SUMMARYObjective: Omalizumab (Xolair), is a recombinant humanised monoclonal anti-immunoglobulin E (IgE) antibody, for the treatment of allergic asthma. This review describes how the correlation between clinical outcomes and a suitable surrogate marker (free serum IgE) led to the development of an individualised dosing strategy for omalizumab. It also demonstrates how subsequent studies using this dosing strategy were able to achieve low levels of IgE and clinical benefit.* Xolair is a registered trade name of Novartis Pharma AG, Basel, Switzerland and Genentech, South San Francisco, California, USAData sources: Published articles and data on file (Novartis PharmaAG, Genentech).Results: Studies in patients with IgE-mediated diseases of the airways have shown that clinical benefit with omalizumab is observed when free IgE levels in serum are reduced to 50ng/ml (20.8 IU ml−1) or less (target 25 ng ml−1 (10.4IU ml−1)). The ability of omalizumab to reduce free IgE levels to such levels is dependent on dose, the patient'sweight and baseline IgE level. To simplify dosing, and ensure that free IgE reduction is achieved, an individualised tiered dosing table was developed from which patients with asthma, depending on weight and starting IgE level, receive omalizumab 150–375 mg by subcutaneous injection every 2 or 4 weeks. This dosing strategy has proved clinically efficacious for improving disease control in patients with allergic asthma, as shown by significantly lower exacerbation rates and decreased dependence on treatment with inhaled corticosteroids, along with improvements in symptoms, lung function and usage of rescue bronchodilators.Conclusions: The clinical efficacy of omalizumab has been optimised through the development of an individualised dosing table that emerged from an understanding of the pharmacodynamics of this agent.

From IgE to anti-IgE: where do we stand?

From IgE to anti-IgE: where do we stand?

Allergens in the pathogenesis of asthma: potential role of anti-immunoglobulin E therapy.

Evidence suggests that allergy is a significant triggering factor in asthma in children and adults alike. In immunoglobulin (Ig) E-mediated allergic reactions, sensitization occurs when allergen-specific B cells are stimulated and switched to IgE antibody production by interleukin (IL)-4 and IL-13 provided by helper T cells type 2 (Th2). The IgE antibodies act by arming cells bearing either the high-affinity (FcepsilonRI) or low-affinity (FcepsilonRII or CD23) receptor. The subsequent interaction of allergen with IgE-FcepsilonRI complexes on mast cells and basophils causes cross-linking of receptors that triggers the release of a variety of inflammatory mediators, cytokines and chemokines. Therefore, the ability to lower circulating free IgE levels is desirable because most individuals are exposed to multiple allergens to which they are sensitive at any given time. Omalizumab (formerly known as rhuMAb-E25) is a recently developed humanized monoclonal anti-IgE antibody directed at the FcepsilonRI binding domain of human IgE. It inhibits binding of IgE to mast cells without provoking mast cell activation. Preliminary clinical data from randomized controlled trials have shown that the addition of omalizumab to standard asthma therapy reduces asthma exacerbations and decreases inhaled corticosteroid and rescue medication use. The compound is also well tolerated. Omalizumab represents a novel therapeutic approach in the management of asthma.

Beyond our pages

Beyond our pages

Omalizumab and the immune system: an overview of preclinical and clinical data

This review discusses the role of immunoglobulin (Ig)E in allergic disease, inhibition of IgE with omalizumab, and the consequences of IgE inhibition (both clinically and in terms of the effect on the immune system). Relevant publications obtained from a literature review. Relevant publications on IgE, allergic disease, and anti-IgE were critically evaluated. IgE plays a key role in allergic diseases such as allergic asthma and allergic rhinitis. Its role in healthy individuals is less well defined. Treatment of allergic asthma and rhinitis with omalizumab, a humanized monoclonal anti-IgE antibody, causes a marked reduction in circulating free IgE levels. This has been shown to reduce symptoms and decrease the need for other medication in patients with these allergic diseases. Anti-IgE treatment with omalizumab did not cause any of the complications that might, in theory, be expected to result from reduction in circulating free IgE, such as adverse effects upon the immune system or other body systems. The limited clinical data currently available suggest that this novel method of treatment for allergic asthma and rhinitis seems to be both effective and well tolerated in clinical use.

The role of IgE in allergen-induced inflammation and the potential for intervention with a humanized monoclonal anti-IgE antibody.

IgE plays a key role in allergic reactions, particularly the early phase response. A humanized monoclonal anti-IgE antibody (omalizumab) that prevents IgE from binding to receptors on mast cells and basophils is undergoing clinical trials in a number of allergic diseases. Following intravenous or subcutaneous administration in humans, omalizumab has a long plasma elimination half-life (1± 4 weeks) and decreases free IgE levels in serum. Omalizumab is well tolerated and shows promise in the treatment of asthma and seasonal allergic rhinitis.

Omalizumab.

* Omalizumab is a recombinant humanised monoclonal antibody which specifically binds to the C epsilon3 domain of immunoglobulin (Ig) E, the site of high-affinity IgE receptor binding. * Improvements in asthma symptoms and health-related quality-of-life, and a significant reduction in the frequency of asthma exacerbations were seen in allergic asthmatic patients treated with omalizumab. * Omalizumab was also effective in the treatment of children with allergic asthma demonstrating improvements in health-related quality-of-life and significant dosage reductions of inhaled corticosteroids. * Administration of omalizumab to patients with allergic rhinitis resulted in a rapid dose-dependent suppression of serum free IgE levels. * Omalizumab significantly improved health-related quality-of-life and nasal symptoms in patients with seasonal allergic rhinitis. Antihistamine requirements were also significantly reduced following treatment. * Adverse events were infrequent in clinical trials of omalizumab, and not significantly different from placebo. The most frequent drug-related event was mild to moderate urticaria.

Recombinant humanized mAb-E25, an anti-IgE mAb, in birch pollen–induced seasonal allergic rhinitis

Background: Allergic rhinitis is a common condition often requiring treatment. Objective: We evaluated whether recombinant humanized (rhu)mAb-E25, a recombinant humanized construct of a murine antibody that binds to circulating IgE, could control symptoms and reduce intake of concomitant medication in seasonal allergic rhinitis (SAR) induced by birch pollen if given subcutaneously in a dose schedule predicted to reduce serum free IgE levels below 25 ng/mL. Methods: We randomly assigned 251 adult subjects with a history of SAR and a positive skin test response to birch pollen to receive 300 mg of rhumAb-E25 or placebo given 2 or 3 times during the season, depending on baseline IgE levels. The primary efficacy variable was the subject's average daily nasal symptom severity score (sneezing, itching, runny, and stuffy nose) from diary data collected over the double-blind treatment period. Secondary efficacy variables included the average number of rescue antihistamine tablets per day, the proportion of days with any SAR medication use, and rhinoconjunctivitis-specific quality of life (QOL). Results: Significant between-treatment differences in favor of rhumAb-E25 were observed in average daily nasal symptom severity scores, the average number of tablets of rescue antihistamines per day, the proportion of days with any SAR medication use, and all domains of QOL. Serum-free IgE levels were markedly lower in rhumAb-E25–treated subjects and were associated with clinical effectiveness. Recombinant humanized mAb-E25 was well tolerated. No anti-rhumAb-E25 antibodies were detected. Conclusion: Compared with placebo, rhumAb-E25 was safe and effective in controlling birch pollen–induced SAR symptoms, with less concomitant medication use and improved QOL. This study shows the therapeutic potential of anti-IgE antibody in SAR. (J Allergy Clin Immunol 2000;106:253-9.)

Down-Regulation of Human Basophil IgE and FCεRIα Surface Densities and Mediator Release by Anti-IgE-Infusions Is Reversible In Vitro and In Vivo

AbstractPreviously, infusions of an anti-IgE mAb (rhumAb-E25) in subjects decreased serum IgE levels, basophil IgE and FcεRIα surface density, and polyclonal anti-IgE and Ag-induced basophil histamine release responses. We hypothesized that these effects would be reversed in vivo by discontinuation of infusions and in vitro by exposing basophils to IgE. Subjects received rhumAb-E25 biweekly for 46 wk. Blood samples taken 0–52 wk after rhumAb-E25 were analyzed for serum IgE and basophil expression of IgE, FcεRIα, and CD32. Basophil numbers were unaffected by infusions. Eight weeks after infusions, free IgE levels rose in vivo but did not reach baseline. Basophil IgE and FcεRIα rose in parallel with free IgE while CD32 was stable. FcεRI densities, measured by acid elution, returned to 80% of baseline, whereas histamine release responses returned to baseline. Basophils cultured with or without IgE or IgG were analyzed for expression of IgE, FcεRIα, and CD32. By 7 days with IgE, expression of IgE and FcεRIα rose significantly, whereas cultures without IgE declined. IgE culture did not effect CD32. IgG culture did not effect expression of any marker. The present results strongly suggest that free IgE levels regulate FcεRIα expression on basophils.

Use of an anti-IgE humanized monoclonal antibody in ragweed-induced allergic rhinitis

Background: Increased serum levels of antigen-specific IgE are often associated with allergic respiratory disorders. RhuMAb-E25, a recombinant humanized monoclonal antibody, decreases free serum IgE by forming biologically inactive immune complexes with free IgE. Objective: We hypothesized that rhuMAb-E25 would decrease total serum IgE and reduce symptoms. Methods: Two hundred forty subjects were enrolled into five groups to determine the safety, tolerance, and efficacy of repeated administration of rhuMAb-E25 in adults with ragweed-induced allergic rhinitis and to explore the pharmacodynamic relationship of rhuMAb-E25 and IgE. One hundred eighty-one subjects received an initial intravenous loading dose (day 0, 1 month before ragweed season), followed by administration of rhuMAb-E25 (in mg/kg body weight) of 0.15 mg/kg subcutaneously, 0.15 mg/kg intravenously, or 0.5 mg/kg intravenously on days 7, 14, 28, 42, 56, 70, and 84. A subcutaneous placebo group and an intravenous placebo group were included. The total evaluation time included the 84-day treatment period, followed by a 42-day observation period. Results: Adverse events were mild, and no differences were observed in the rates between the three active and two placebo treatment groups. Ragweed-specific IgE levels correlated with symptom scores. RhuMAb-E25 decreased serum free IgE levels in a dose- and baseline IgE–dependent fashion. However, only 11 subjects had IgE levels that were suppressed to undetectable levels (≤24 ng/ml), a sample too small to demonstrate significant differences and clinical efficacy. Thus the case for efficacy was not proven. Nonetheless, the study confirms that it is safe to repeatedly administer rhuMAb-E25 over a period of months. Conclusions: Because rhuMAb-E25 decreased serum free IgE in a dose-dependent fashion and because symptom scores correlated with antigen-specific IgE levels, the results suggest that if given in adequate doses, rhuMAb-E25 should be an effective therapy for allergic diseases. (J Allergy Clin Immunol 1997;100:110-21.)

Down-regulation of Fc(epsilon)RI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody.

Treatment of allergic disease by decreasing circulating IgE with anti-IgE Abs is currently under clinical study. Based on previous unrelated studies, it appeared likely that Fc(epsilon)RI expression on basophils and mast cells might also be regulated by levels of circulating IgE Ab. Therefore, the expression of IgE and Fc(epsilon)RI on human basophils was examined in 15 subjects receiving humanized anti-IgE mAb intravenously. Treatment with the anti-IgE mAb decreased free IgE levels to 1% of pretreatment levels and also resulted in a marked down-regulation of Fc(epsilon)RI on basophils. Median pretreatment densities of Fc(epsilon)RI were approximately 220,000 receptors per basophil and after 3 mo of treatment, the densities had decreased to a median of 8,300 receptors per basophil. Flow cytometric studies, conducted in parallel, showed similar results and also showed in a subset of 3 donors that receptors decreased with a t1/2 of approximately 3 days. The responsiveness of the cells to IgE-mediated stimulation using anti-IgE Ab was marginally decreased (approximately 40%) while the response of the same cells to stimulation with dust mite Ag, Dermatophagoides farinae, was reduced by approximately 90%. One possible explanation for these results is that Fc(epsilon)RI density is directly or indirectly regulated by plasma-free IgE levels.