Slide 1 : Anti- IgE Therapy in Asthma Tarek Essawy
Assistant Lecturer, Chest Department
Banha University
Slide 2 : INTRODUCTION Immunoglobulin E (IgE) plays a central role in the pathogenesis of allergic diseases, including asthma . For this reason, IgE-mediated immunologic pathways have long represented an attractive target for therapeutic agents in asthma.
Slide 3 : ROLE OF IgE IN ASTHMA Most asthmatic patients have elevated circulating IgE concentrations when levels are adjusted for age . Atopy represents the formation of specific IgE in high concentration in response to common inhalant allergens, such as house dust mites and pollens.
Slide 4 : IgE is produced by B lymphocytes under the direction of two cytokines:
Interleukin (IL)-4 and the closely related IL-13, which are produced by Th2 cells, the subset of T-helper lymphocytes that predominate in atopy .
Slide 5 : IgE formation is markedly enhanced by the interaction of two co-stimulatory molecules:
A CD40 ligand expressed on the Th2 cells that interacts with CD40 on B cells. Specific IgE formed from these committed B cells circulates and binds to specific high affinity receptors (Fc-epsilon-RI) on the surface of mast cells and basophiles.
Slide 6 : Cross-bridging of these IgE molecules by allergenic peptides results in the activation of mast cells, with release of preformed mediators such as histamine, and increased synthesis of lipid mediators such as cysteinyl-leukotrienes .
Slide 7 : These mast cell mediators result in bronchoconstriction and plasma exudation. Thus, IgE plays a central role in the mechanism of immediate bronchoconstriction in allergic asthmatic patients after inhalation of allergen.
Slide 8 : A similar mechanism is also involved in exercise-induced asthma, and probably during acute exacerbations of asthma following upper respiratory tract viral infections. Circulating IgE also binds to low affinity IgE receptors (Fc-epsilon-RII or CD23), found on B-
lymphocytes,monocytes,macrophags, dendritic cells, and possibly eosinophils .
Slide 9 : Allergen may also interact with this bound IgE, although higher concentrations of allergenic proteins may be required to result in cell activation. By this mechanism, IgE may activate other cell types in addition to mast cells.
Slide 10 : Most asthmatic patients are atopic, with one or more positive skin tests to common allergens and increased specific IgE concentrations in serum. Indeed, atopy is the strongest risk factor for developing Asthma
Slide 11 : A small proportion of asthmatic patients have intrinsic asthma with negative skin tests, normal levels of total IgE, and no circulating specific IgE. However, these patients may have local formation of IgE, suggesting that IgE may be abnormal in all asthmatic patients, irrespective of whether they are atopic .
Slide 12 : ANTI-IgE THERAPY IN ASTHMA A recombinant humanized antibody
(omalizumab) that binds IgE with high affinity has been developed for the treatment of allergic diseases . The antibody has a molecular weight of approximately 149 kilodaltons .
Slide 13 : Release of IgE Plasma cell B lymphocyte -switch Asthma exacerbation Allergic
inflammation:eosinophils and lymphocytes Allergens Mast cells
Basophils Allergic
mediators Overview of the allergic inflammatory cascadein patients with IgE-mediated asthma 13
Omalizumab mechanism of actionin IgE-mediated asthma : Asthma exacerbation Omalizumab mechanism of actionin IgE-mediated asthma Perennial
aeroallergens Omalizumab Binds to free IgE, reducing cell-bound IgE Reduces asthma exacerbations and symptoms Plasma cell B lymphocyte -switch Allergic
mediators Release of IgE Mast cells
Basophils Allergic
inflammation:eosinophils and lymphocytes 14
Slide 15 : An important property of this antibody is that it binds to the C-epsilon-3 domain of circulating IgE but does not bind to Fc-epsilon-RI, and therefore does not activate mast cells or basophils . The antibody is specific to IgE and does not bind to IgG or IgA.
Slide 16 : Omalizumab is effective when administered by subcutaneous injection every 2 to 4 weeks in a dose that is determined by the levels of serum IgE. Omalizumab can be considered as an add-on therapy to reduce or discontinue treatment with oral corticosteroids in patients with severe asthma.
Slide 17 : Omalizumab may also be indicated in patients who have severe allergic symptoms of asthma and rhinitis and who have very high circulating levels of IgE.
Slide 18 : Clinical Studies Aerosolized omalizumab (10 mg) is ineffective in protecting against allergen challenge and has no effect on circulating IgE . This suggests that anti-IgE therapy needs to be given systemically. Also significant reduction in circulating IgE is necessary for clinical efficacy
Slide 19 : In contrast, parenteral use of the antibody appears to significantly reduce the concentration of circulating IgE and affect markers of asthma severity. In human subjects with atopy, omalizumab induces a rapid and sustained fall in serum IgE of 96 percent following a 100 mg intravenous dose, with a mean recovery of 50 percent by 39 days .
Slide 20 : Omalizumab therapy has also been associated with improved quality of life and fewer emergency room visits in patients with severe allergic asthma . These results suggest that omalizumab may have a role as an additional treatment in patients with steroid-dependent asthma, who are currently difficult to treat with other therapies. .
Slide 21 : In one study of atopic subjects, free IgE dropped after each twice-weekly dose down to concentrations that were 1 percent of the starting IgE level. A marked down-regulation of Fc-epsilon-RI was found on basophils, with concomitant reduction of histamine release in response to allergen
Slide 22 : This downregulation of Fc-epsilon-RI may be an important aspect of the beneficial response to omalizumab. Omalizumab given intravenously, twice weekly for 10 weeks, reduced the response to inhaled allergen and had a small effect upon methacholine reactivity ..
Slide 23 : Intravenous omalizumab also reduced the early (40 percent reduction) and late response (63 percent reduction) to allergen compared to placebo in patients with mild asthma, in whom there was a >90 percent fall in circulating IgE
Slide 24 : There was also a reduction in eosinophils in induced sputum and in airway responsiveness after omalizumab treatment, suggesting an antiinflammatory effect.
Slide 25 : This is somewhat unexpected and suggests that, in addition to an inhibitory effect on mast cell activation, there also must be an additional effect on other inflammatory cells, such as lymphocytes, macrophages, or eosinophils
Slide 26 : Clinical use — In June 2003, the Food and Drug Administration in the United States approved omalizumab for subcutaneous use in moderate-to-severe asthmatics with a positive skin test (or demonstrated in vitro sensitivity) to aeroallergen and incomplete symptom control with inhaled corticosteroid treatment .
Slide 27 : Omalizumab is approved for use in patients 12 years of age and above; in the future, the manufacturer is expected to seek approval for children 6 to 11 years of age. Omalizumab has not been approved for use in other allergic diseases or patient populations, and should not be initiated in the setting of an acute exacerbation of asthma.
Slide 28 : Therapy generally requires a dose of 150 to 375 mcg every two to four weeks. Peak serum concentration is reached in 7 to 8 days . No more than 150 mcg should be administered at a single site, to prevent local reactions.
Slide 29 : The cost of omalizumab therapy will exceed that of other asthma treatments; the cost is $10,000 to $12,000 per year . Because of its high cost omalizumab is only likely to be cost-effective in patients with severe persistent asthma complicated by frequent exacerbations requiring hospitalization .
Slide 30 : ANTI-IgE THERAPY IN OTHER DISEASES Because IgE plays a critical role in other allergic diseases, it might be expected that omalizumab may be beneficial in the treatment of allergic rhinitis and atopic dermatitis.
Slide 31 : Omalizumab is effective in reducing symptoms and the use of concomitant antihistamine therapy in seasonal rhinitis . The beneficial effect is directly related to the reduction in free circulating IgE .
Slide 32 : It may not be effective in atopic dermatitis at currently recommended doses, as IgE levels are usually too high to neutralize.
Slide 33 : ADVERSE EFFECTS To date, all studies have indicated that omalizumab is well tolerated. An urticarial skin rash has been reported in a small number of patients . Less than 0.1 percent of patients receiving omalizumab developed anaphylaxis that could not be ascribed to any other agent.
Slide 34 : There is no evidence of loss of effect with continued treatment and no evidence for the development of antibodies.
Slide 35 : Concerns that reducing IgE might impair immunity to parasitic infections have been addressed experimentally in mice infected with Nippostrongylus and Schistosoma; surprisingly, animals treated with omalizumab have shown increased rather than decreased elimination of parasites .
Slide 36 : Thrombocytopenia was noted in experiments in which monkeys received 3 to 27 times the maximum human clinical dose, but has not been a significant problem in reported human trials to date. In clinical trials the observed incidence of malignancy among omalizumab -treated patients (0.5%) was numerically higher than among patients in control groups (0.2%). .
Slide 37 : The observed malignancies in omalizumab -treated patients were a variety of types, with breast, non-melanoma skin, prostate, melanoma, and parotid occurring more than once
Slide 38 : OTHER STRATEGIES TO REDUCE IgE Several other therapeutic approaches to reduce IgE concentrations or effects are in development. Corticosteroids do not inhibit IgE synthesis by B lymphocytes and may even increase circulating IgE by enhancing the expression of CD40 ligand .
Slide 39 : Cytokine modulators — IgE synthesis is suppressed by inhibition of the cytokines IL-4 or IL-13 and by interferon-gamma and IL-12, which switch the balance from Th2 towards Th1 cells . Several efforts have been made to influence IgE production at these upstream steps:
Slide 40 : Soluble human recombinant IL-4 receptor (altrakincept) given by inhalation has some steroid-sparing effect in asthma, but the effects on circulating IgE have not been reported .
Soluble IL-13 receptor is in clinical development, but no clinical results have been reported.
Slide 41 : IL-12 reduces circulating eosinophils in asthma, presumably via an inhibitory effect on IL-5 production by Th2 cells, but the effect on circulating IgE is not known . However, this treatment is not well tolerated and is not being actively developed as a therapy.
Slide 42 : Interferon-gamma does not appear to be effective in the treatment of asthma, at least when given by inhalation .
Slide 43 : Immunotherapy
Specific immunotherapy reduces specific IgE, but is not very effective in the control of asthma.
Safer approaches to specific immunotherapy using peptides that are recognized by T-lymphocytes are now in development .