anti-IgE Antibody Research Articles

Clinical outcomes of patients with idiopathic anaphylaxis receiving omalizumab

Idiopathic anaphylaxis involves episodes of anaphylaxis without a specific trigger. Management includes antihistamines and mast cell stabilizers, but some patients fail to respond to this treatment. Omalizumab, an anti-IgE monoclonal antibody, is not approved for treatment of idiopathic anaphylaxis, but has been used in patients with idiopathic anaphylaxis under concurrent diagnoses of allergic asthma or chronic idiopathic urticaria. We describe the clinical response to omalizumab in patients with idiopathic anaphylaxis without evidence of mast cell clonality.

Rituximab as Treatment of Chronic Idiopathic Urticaria

Conventional treatment of chronic idiopathic urticaria involves high doses of antihistamines followed by omalizumab in refractory cases, however, there are patients who do not achieve resolution of symptoms despite both of these therapies. The following case series describes two cases of chronic idiopathic urticaria successfully treated with rituximab. The first patient is a 43 year-old woman with psoriatic arthritis and autoimmune thyroiditis who presented to us with chronic idiopathic urticaria. She was found to have elevated levels of anti-IgE receptor antibodies with levels greater than maximum level of detection. She was unresponsive to high doses of antihistamines, cyclosporine, prednisone, dapsone, mycophenolate mofetil, hydroxychloroquine, and omalizumab and ultimately trialed on rituximab with complete resolution of urticaria. Our second patient is a 49 year-old woman with multiple sclerosis, allergic rhinitis, and atopic dermatitis who was referred with humoral immunodeficiency. She was diagnosed with common variable immune deficiency and started on SQ immune globulin therapy. She also had long-standing generalized urticaria refractory to antihistamines which responded to rituximab started by her neurologist for a flare of her multiple sclerosis. Use of rituximab in treatment of chronic idiopathic urticaria is not well documented in literature today and should be entertained as possible therapy for cases of treatment-resistant chronic urticaria, especially in the setting of other autoimmune conditions.

MiR103a-3p in extracellular vesicles from FcεRI-aggregated human mast cells enhances IL-5 production by group 2 innate lymphoid cells

Mast cells (MCs) are key regulators of IgE-mediated allergic inflammation. Cell-derived extracellular vesicles (EVs) contain bioactive compounds such as microRNAs. EVs can transfer signals to recipient cells, thus using a novel mechanism of cell-to-cell communication. However, whether MC-derived EVs are involved in FcεRI-mediated allergic inflammation is unclear. We sought to investigate the effect of EVs derived from FcεRI-aggregated human MCs on the function of human group 2 innate lymphoid cells (ILC2s). Human cultured MCs were sensitized with and without IgE for 1 hour and then incubated with anti-IgE antibody, IL-33, or medium alone for 24 hours. EVs in the MC supernatant were isolated by using ExoQuick-TC. Coculture of ILC2s with EVs derived from the FcεRI-aggregated MCs significantly enhanced IL-5 production and sustained upregulation of IL-5 mRNA expression in IL-33-stimulated ILC2s, but IL-13 production and IL-13 mRNA expression were unchanged. miR103a-3p expression was upregulated in IL-33-stimulated ILC2s that had been cocultured with EVs derived from anti-IgE antibody-stimulated MCs. Transduction of an miR103a-3p mimic to ILC2s significantly enhanced IL-5 production by IL-33-stimulated ILC2s. miR103a-3p promoted demethylation of an arginine residue of GATA3 by downregulating protein arginine methyltransferase 5 (PRMT5) mRNA. Reduction of protein arginine methyltransferase 5 expression in ILC2s by using a small interfering RNA technique resulted in upregulation of IL-5 production by IL-33-stimulated ILC2s. Furthermore, the level of miR103a-3p expression was significantly higher in EVs from sera of patients with atopic dermatitis than in EVs from nonatopic healthy control subjects. Eosinophilic allergic inflammation may be exacerbated owing to ILC2 activation by MC-derived miR103a-3p.

Ligelizumab: A promising option on the horizon for the management of chronic spontaneous urticaria

Chronic spontaneous urticaria may pose challenges for the treatment in some patients. Different options for the management of chronic urticaria include second-generation antihistamines, leukotriene receptor antagonists, omalizumab (anti-IgE antibody), and immunosuppressants. Omalizumab, a monoclonal antibody, is a valuable option for patients not responding to up-dosing (up to 4 times) of second-generation antihistamine. However, in about one-fourth of the patients, omalizumab may not be effective in controlling symptoms. Considering this, there is a need to identify the drugs for effective treatment. Ligelizumab is a novel anti-IgE monoclonal antibody with higher affinity to IgE than omalizumab. In phase 2b clinical trial, it is found to be effective and well tolerated in patients with chronic spontaneous urticaria. When approved, it may be beneficial for patients who cannot receive or have suboptimal efficacy with omalizumab.

Anti-IgE: A treatment option in allergic rhinitis?

Background: Allergic rhinitis (AR) is the most common IgE-mediated allergic disease. Multiple clinical trials have demonstrated promising results on the AR treatment with biologics, in particular with the use of omalizumab – an anti-IgE antibody. Omalizumab has also been established in the routine management of allergic asthma and chronic idiopathic urticaria. However, currently there is no approved license for the use of biologics in AR in Germany. Materials and methods: A systematic literature review has been completed including randomized controlled trials, meta-analyses, and reviews on the treatment of AR with omalizumab. Results: The systematic review demonstrates strong evidence supporting the use of omalizumab in the treatment of AR with regard to symptom control, safety profile, and management of comorbidities. Conclusion: Omalizumab is a good and safe option in the treatment of AR in terms of symptom control and the management of pre-existing comorbidities. Further clinical trials with other biologics in the management of AR are needed and are expected to follow soon.

Severe asthma with fungal sensitization

Bronchial asthma is an inflammatory disease of the airways, which may be worsened due to many extrinsic factors. The most common trigger is the continuous exposure to allergens, of which fungal agents are important factors. A new phenotype of asthma called severe asthma with fungal sensitization (SAFS) has been described. It is diagnosed by the presence of severe asthma, fungal sensitization, and absence of allergic bronchopulmonary aspergillosis. SAFS is more of a diagnosis of exclusion. Treatment of SAFS initially should be similar to that of severe asthma including humanized anti-IgE monoclonal antibody and other biologics. These patients usually do not have their symptoms relieved with conventional treatment of severe asthma, i.e. high-dose inhaled corticosteroids and long-acting bronchodilators. Prolonged use of oral corticosteroids and pulse high-dose intravenous corticosteroid is effective. There are some evidence implicating the role of antifungal agents including itraconazole, but its use as a specific therapy requires further studies.

Potential Role of Mast Cells in Regulating Corticosteroid Insensitivity in Severe Asthma.

The mechanisms driving corticosteroid insensitivity in asthma are still unclear although evidence points toward a potential role of lung mast cells. Indeed, a number of in vitro studies using various cell types showed that different mediators produced by activated mast cells, including cytokines, have the capacity to interfere with the therapeutic action of corticosteroids. In patients with severe allergic refractory asthma, the anti-IgE monoclonal antibody (mAb), Omalizumab, has been shown to be associated with a marked reduction in inhaled and systemic use of corticosteroids, further suggesting a key role of mast cells in the poor response of patients to these drugs. The present chapter will discuss the possible underlying mechanisms by which mast cells could contribute to reducing corticosteroid sensitivity seen in patients with severe asthma.

Omalizumab in chronic urticaria; real-life data of 6-year-experience

Background: Chronic urticaria (CU) is defined as the persistence of urticarial lesions for more than 6 weeks. Omalizumab, a human monoclonal anti IgE antibody, has been used as a new therapeutic option in CU patients unresponsive to high-dose second-generation antihistamines. Aims and Objectives: This study is aimed to examine the clinical and demographic characteristics of CU patients treated with omalizumab in our clinic and to define parameters related to therapeutic response. Materials and Methods: Patients who were followed up with the diagnosis of CU between January 2014 and June 2020 were evaluated retrospectively. The data obtained from patients’ electronic files were analyzed using SPSS23 program. Results: 167 patients (125 female, 42 male) were included. The mean age was 45.34 ± 14.76 years. The mean disease duration at the onset of omalizumab was found to be 47.41 ± 63.26 months. Complete response to treatment was observed in 45.9%, 48%, and 52% of patients at 3rd, 6th, and 12th months of omalizumab treatment, respectively. The baseline total IgE level was evaluated in 107 patients and a statistically significant correlation was observed between complete response to treatment at 3rd month and higher baseline total IgE levels (P < 0.001). Conclusion: Omalizumab provided a significant therapeutic response and the patients did not need any other treatment, while patients with high pretreatment IgE levels showed a better and earlier response. These results may guide clinicians in predicting patients’ response to omalizumab.

Use of biologics in chronic spontaneous urticaria - beyond omalizumab therapy?

In chronic spontaneous urticaria (CSU), itchy wheals, angioedema, or both occur regularly, often daily, and for years. An effective therapy for CSU aims at achieving complete symptom control. The current guideline for the management of CSU patients recommends non-sedative anthistamines in standard or up to 4-fold higher dosages as 1 and 2 line treatment. For most CSU patients this treatment is not sufficient; for them, the anti-IgE antibody omalizumab is the therapy of choice. Although good to very good symptom control can be achieved in most cases, there are many patients with insufficient response. For these patients, but also as an alternative to therapy with omalizumab, numerous other biologicals are currently under development. In this review, we provide an overview of possible future biologic therapies for chronic urticaria.

Use of biologics in allergen immunotherapy.

Biologics are drugs that are derived or synthesized from biological sources. A particular class are recombinant monoclonal antibodies. Their targeted application against distinct molecules of intercellular communication is of significant relevance in the treatment of tumor, inflammatory, or allergic diseases. But also in the context of allergen immunotherapy (AIT) they can be of special value. This is exemplified by the anti-IgE antibody omalizumab, which allows to achieve allergen tolerance in patients suffering from severe allergic reactions and increased risk of AIT-induced anaphylaxis. Furthermore, omalizumab administration during AIT effectively lowers the rsik of allergic side effects. This is demonstrated by a variety of studies and case reports of patients suffering either form respiratory, food, or insect venom allergy. Besides a direct blocking of IgE-mediated effects, T-cellular immune mechanisms might also be involved. Another interesting option is the applcation of recombinant IgG antibodes directed against specific epitopes of an allergen. Similar to AIT-induced IgG antibodies they can prevent the binding of allergens to IgE-antibodes as well as the hereby elicited allergic reactions.

Targeting the FcεRI Pathway as a Potential Strategy to Prevent Food-Induced Anaphylaxis

Despite attempts to halt it, the prevalence of food allergy is increasing, and there is an unmet need for strategies to prevent morbidity and mortality from food-induced allergic reactions. There are no known medications that can prevent anaphylaxis, but several novel therapies show promise for the prevention of food-induced anaphylaxis through targeting of the high-affinity IgE receptor (FcϵRI) pathway. This pathway includes multiple candidate targets, including tyrosine kinases and the receptor itself. Small molecule inhibitors of essential kinases have rapid onset of action and transient efficacy, which may be beneficial for short-term use for immunotherapy buildup or desensitizations. Short courses of FDA-approved inhibitors of Bruton’s tyrosine kinase can eliminate IgE-mediated basophil activation and reduce food skin test size in allergic adults, and prevent IgE-mediated anaphylaxis in humanized mice. In contrast, biologics may provide longer-lasting protection, albeit with slower onset. Omalizumab is an anti-IgE antibody that sequesters IgE, thereby reducing FcϵRI expression on mast cells and basophils. As a monotherapy, it can increase the clinical threshold dose of food allergen, and when used as an adjunct for food immunotherapy, it decreases severe reactions during buildup phase. Finally, lirentelimab, an anti-Siglec-8 antibody currently in clinical trials, can prevent IgE-mediated anaphylaxis in mice through mast cell inhibition. This review discusses these and other emerging therapies as potential strategies for preventing food-induced anaphylaxis. In contrast to other food allergy treatments which largely focus on individual allergens, blockade of the FcϵRI pathway has the advantage of preventing clinical reactivity from any food.

Role of IgE-FcεR1 in Pathological Cardiac Remodeling and Dysfunction.

Immunoglobulin E (IgE) belongs to a class of immunoglobulins involved in immune response to specific allergens. However, the roles of IgE and IgE receptor (FcεR1) in pathological cardiac remodeling and heart failure are unknown. Serum IgE levels and cardiac FcεR1 expression were assessed in diseased hearts from human and mouse. The role of FcεR1 signaling in pathological cardiac remodeling was explored in vivo by FcεR1 genetic depletion, anti-IgE antibodies, and bone marrow transplantation. The roles of the IgE-FcεR1 pathway were further evaluated in vitro in primary cultured rat cardiomyocytes and cardiac fibroblasts (CFs). RNA sequencing and bioinformatic analyses were used to identify biochemical changes and signaling pathways that are regulated by IgE/FcεR1. Serum IgE levels were significantly elevated in patients with heart failure as well as in 2 mouse cardiac disease models induced by chronic pressure overload via transverse aortic constriction and chronic angiotensin II infusion. Interestingly, FcεR1 expression levels were also significantly upregulated in failing hearts from human and mouse. Blockade of the IgE-FcεR1 pathway by FcεR1 knockout alleviated transverse aortic constriction- or angiotensin II-induced pathological cardiac remodeling or dysfunction. Anti-IgE antibodies (including the clinical drug omalizumab) also significantly alleviated angiotensin II-induced cardiac remodeling. Bone marrow transplantation experiments indicated that IgE-induced cardiac remodeling was mediated through non-bone marrow-derived cells. FcεR1 was found to be expressed in both cardiomyocytes and CFs. In cultured rat cardiomyocytes, IgE-induced cardiomyocyte hypertrophy and hypertrophic marker expression were abolished by depleting FcεR1. In cultured rat CFs, IgE-induced CF activation and matrix protein production were also blocked by FcεR1 deficiency. RNA sequencing and signaling pathway analyses revealed that transforming growth factor-β may be a critical mediator, and blocking transforming growth factor-β indeed alleviated IgE-induced cardiomyocyte hypertrophy and cardiac fibroblast activation in vitro. Our findings suggest that IgE induction plays a causative role in pathological cardiac remodeling, at least partially via the activation of IgE-FcεR1 signaling in cardiomyocytes and CFs. Therapeutic strategies targeting the IgE-FcεR1 axis may be effective for managing IgE-mediated cardiac remodeling.

Prise en charge de l’allergie chez les patients asthmatiques sévères: Management of allergy in severe asthma patients

Allergic asthma is the most common phenotype in asthma including severe asthma. Allergy work-up in patients with asthma regardless of severity is therefore a crucial part of the management. A complete history associated with skin prick tests are systematic in all asthma patients. The certainty of a link between allergy and asthma symptoms is complex in clinical practice. Allergic comorbidities such as allergic rhinitis, atopic dermatitis or food allergy are common in severe asthma patients, especially the youngest ones. A global management integrating the treatment of these allergic comorbidities is essential to improve the quality of life in asthma patients.Major advances regarding the underlyning pathophysiological mechanisms of severe asthma have led to expand the therapeutic arsenal. Despite approval of biological therapies, non-pharmacological intervention of the environment should not be forgotten. Regarding biological therapies, omalizumab, an anti-IgE antibody, has been used for nearly 20 years in severe allergic asthma. It also has beneficial effect on some allergic comorbidities such as allergic rhinitis and food allergy. Anti-interleukin 5 (IL5) (mepolizumab) or anti-IL5 receptor (benralizumab) antibodies are used in patients with severe asthma and blood eosinophil count ≥ 0.3 G / l. Dupilumab, anti-interleukin 4 receptor antibody, has been recently approved in severe asthma. It is already used in severe atopic dermatitis and studies in other allergic comorbidities are underway.© 2020 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Ligelizumab for Chronic Spontaneous Urticaria

M Maure, AM Gimenez-Arnau, G Sussman. N Engl J Med. 2019;381(14):1321–371332 To determine the efficacy of a next generation, high affinity, humanized monoclonal anti-IgE antibody in the treatment of chronic spontaneous urticaria (CSU). Patients (n = 382) were 18–75 years old with moderate to severe CSU who were not controlled with maximum medical management. The patients were randomized 2:2:2:1:1:1 to receive one of the following subcutaneous regimens: 240 mg of ligelizumab every four weeks, 72 mg of ligelizumab every four weeks, 24 mg of ligelizumab every four weeks, 300 mg of omalizumab every four weeks, placebo every four weeks, or a single 120 mg dose of ligelizumab at week zero followed by placebo …

An Omalizumab Biobetter Antibody With Improved Stability and Efficacy for the Treatment of Allergic Diseases.

The critical role of IgE in allergic diseases is well-documented and clinically proven. Omalizumab, a humanized anti-IgE antibody, was the first approved antibody for the treatment of allergic diseases. Nevertheless, omalizumab still has some limitations, such as product instability and dosage restriction in clinical application. In this study, we attempted to develop an omalizumab biobetter antibody with the potential to overcome its limitations. We removed two aspartic acid isomerization hotspots in CDRs of omalizumab to improve antibody candidate’s stability. Meanwhile, several murine amino acids in the framework region of omalizumab were replaced with human source to reduce the potential immunogenicity. Yeast display technology was then applied to screen antibody candidates with high binding affinity to IgE. Moreover, YTE mutation in Fc fragment was introduced into the candidates for extending their serum half-life. A lead candidate, AB1904Am15, was screened out, which showed desired biophysical properties and improved stability, high binding affinity and elevated potency in vitro, prolonged half-life in human FcRn transgenic mouse, and enhanced in vivo efficacy in cynomolgus monkey asthma model. Overall, our study developed a biobetter antibody of omalizumab, AB1904Am15, which has the potential to show improved clinical benefit in the treatment of allergic diseases.

Effects of Omalizumab Treatment in Patients With Recalcitrant Nasal Polyposis and Mild Asthma: A Multicenter Retrospective Study.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a clinical entity with specific features that impacts significantly on patient quality of life (QoL). CRSwNP is often associated with asthma and is difficult to control and manage despite pharmacological and/or surgical treatment. Omalizumab, a monoclonal anti-IgE antibody, has emerged as a putative therapeutic option. To evaluate the effects of omalizumab on nasal polyp (NP) size and QoL assessed by Sino-Nasal Outcome Test-22 (SNOT-22) in patients with recalcitrant CRSwNP and mild asthma. A multicenter retrospective analysis of patient data from the Community of Valencia (Spain) was performed. Adult patients with recalcitrant CRSwNP and comorbid mild asthma receiving compassionate use of omalizumab were included. NP size measured by total nasal endoscopic polyp score (TPS) and QoL evaluated through the SNOT-22 questionnaire were assessed at baseline and monthly over 12 months. An ordinal regression model was built to analyze the results. A total of 23 CRSwNP patients with a mean age (± SD) of 54.78 ± 9.46 years were included. Nineteen suffered from aspirin-exacerbated respiratory disease (AERD). In all patients, a significant and sustained reduction in TPS was observed over time, accompanied by improvements in QoL reflected in lower SNOT-22 scores. In the ordinal regression model, time but not total IgE, age or tissue eosinophilia impacted on NP size and SNOT-22 outcomes. Additionally, improvements in QoL were not explained by reductions in the size of polyps. Omalizumab was effective for the treatment of patients with recalcitrant CRSwNP and mild asthma, even when AERD was present, by reducing NP size and improving QoL; treatment time was a key factor. SNOT-22 improvements were not explained by decreases in TPS, indicating that omalizumab may be effective in all patients, regardless of polyp size.

Treatment with the anti-IgE monoclonal antibody omalizumab in women with asthma undergoing fertility treatment: a proof-of-concept study—The PRO-ART study protocol

IntroductionAsthma is associated with prolonged time to pregnancy and a higher need for fertility treatment. However, the mechanism underlying this association remains incompletely understood. Previous research points to asthma-driven systemic...

D101 EFFICACY OF LIGELIZUMAB IN PATIENTS WITH CHRONIC SPONTANEOUS URTICARIA INADEQUATELY CONTROLLED WITH OMALIZUMAB

In the Phase 2b core study, ligelizumab, a next generation high-affinity humanized monoclonal anti-IgE antibody, was effective in patients with chronic spontaneous urticaria (CSU) inadequately controlled by H1-antihistamines. This analysis evaluates the response to ligelizumab, during the Phase 2b extension study, in patients who did not achieve complete urticaria control with omalizumab in the core study.

IgE Epitope Profiling for Allergy Diagnosis and Therapy - Parallel Analysis of a Multitude of Potential Linear Epitopes Using a High Throughput Screening Platform.

Immunoglobulin E (IgE) is pivotal for manifestation and persistence of most immediate-type allergies and some asthma phenotypes. Consequently, IgE represents a crucial target for both, diagnostic purposes as well as therapeutic approaches. In fact, allergen-specific immunotherapy – aiming to re-route an IgE-based inflammatory response into an innocuous immune reaction against the allergen – is the only curative approach for IgE-mediated allergic diseases known so far. However, this requires the cognate allergen to be known. Unfortunately, even in well-characterized allergics or asthmatics, often just a small fraction of total IgE can be assigned to specific target allergens. To overcome this knowledge gap, we have devised an analytical platform for unbiased IgE target epitope detection. The system relies on chemically produced random peptide libraries immobilized on polystyrene beads (“one-bead-one-compound (OBOC) libraries”) capable to present millions of different peptide motifs simultaneously to immunoglobulins from biological samples. Beads binding IgE are highlighted with a fluorophore-labeled anti-IgE antibody allowing fluorescence-based detection and isolation of positives, which then can be characterized by peptide sequencing. Setting-up this platform required an elaborate optimization process including proper choice of background suppressants, secondary antibody and fluorophore label as well as incubation conditions. For optimal performance our procedure involves a sophisticated pre-adsorption step to eliminate beads that react nonspecifically with anti-IgE secondary antibodies. This step turned out to be important for minimizing detection of “false positive” motifs that otherwise would erroneously be classified as IgE epitopes. In validation studies we were able to retrieve artificial test-peptide beads spiked into our library by using IgE directed against those test-peptides at physiological concentrations (≤20 IU/ml of specific IgE), and disease-relevant bead-bound epitopes of the major peanut allergen Ara h 2 by screening with sera from peanut allergics. Thus, we established a platform with which one can find and validate new immunoglobulin targets using patient material which displays a largely unknown immunoglobulin repertoire.

Evaluating nonadherence to preventer inhaler therapy in severe asthmatic patients receiving omalizumab.

Asthma is one of the most common chronic diseases worldwide and can often be controlled by existing treatments, but in the 5%-10% of patients with severe asthma, control is frequently more challenging. The aim of this paper is to evaluate the adherence to preventer inhaler therapy in severe asthmatic patients receiving omalizumab, a recombinant humanized monoclonal anti-IgE antibody indicated for moderate-to-severe asthma. This study included 29 patients who were receiving omalizumab treatment as maintenance therapy. All patients completed the six question Turkish Modified Morisky Scale. In addition, patients were classified by adherence to their prescribed preventer therapy, based on pharmaceutical and medical device institution records from the preceding one year. Of the 29 enrolled patients, 24.1% had NSAID-exacerbated respiratory disease; 75.9% were female and median age was 47.2±12.99years. Severe asthma patients demonstrated high levels of motivation (98.8%, n=28) and knowledge (86.2%, n=22) about asthma treatment. Nevertheless, the rate of nonadherence to preventer inhaler therapy was only 34.5% (n=10). There were no significant differences among the characteristics of the patients that might affect the adherence to inhaler therapy. In patients with severe asthma, suboptimal adherence to preventer inhaler therapy is common before and after omalizumab treatment. Although patients have high levels of motivation and knowledge about asthma treatment, adherence to inhaler preventer therapy declined after omalizumab therapy. Given these findings, it is important to decide whether preventer inhaler therapy should be continued as monotherapy or be discontinued inpatients exhibiting impaired adherence to biological agents, such as omalizumab.