Ligelizumab treatment for severe asthma: learnings from the clinical development programme

Trischler, Jordis; Bottoli, Ivan; Janocha, Reinhold; Heusser, Christoph; Jaumont, Xavier; Lowe, Philip J.; Gautier, Aurelie; Pethe, Abhijit; Woessner, Ralph; Zerwes, Hans‐Günter; Zielen, Stefan

doi:10.1002/cti2.1255

Cited by 28 publications

(23 citation statements)

References 32 publications

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“…Ligelizumab performs better than omalizumab in inhibition of IgE synthesis, reportedly due to its engagement with CD23-bound IgE, forming aggregate complexes that omalizumab is not involved with (35). Yet, the same interaction with IgE-CD23 complexes has been cited to possibly mimic IgE-allergen complexes that triggered eosinophilic lung inflammation in the treatment of allergic asthma (35,68). Whether this truly occurs with ligelizumab or is applicable to other anti-IgE mAbs remains to be elucidated.…”

Section: Ige Protein and Ige Mrna Expression In Pbmcs Treated With Ub...mentioning

confidence: 99%

IgE-neutralizing UB-221 mAb, distinct from omalizumab and ligelizumab, exhibits CD23-mediated IgE downregulation and relieves urticaria symptoms

Kuo¹,

Li²,

Chen³

et al. 2022

Journal of Clinical Investigation

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Over the last 2 decades, omalizumab is the only anti-IgE antibody that has been approved for asthma and chronic spontaneous urticaria (CSU). Ligelizumab, a higher-affinity anti-IgE mAb and the only rival viable candidate in late-stage clinical trials, showed anti-CSU efficacy superior to that of omalizumab in phase IIb but not in phase III. This report features the antigenic-functional characteristics of UB-221, an anti-IgE mAb of a newer class that is distinct from omalizumab and ligelizumab. UB-221, in free form, bound abundantly to CD23-occupied IgE and, in oligomeric mAb-IgE complex forms, freely engaged CD23, while ligelizumab reacted limitedly and omalizumab stayed inert toward CD23; these observations are consistent with UB-221 outperforming ligelizumab and omalizumab in CD23-mediated downregulation of IgE production. UB-221 bound IgE with a strong affinity to prevent FcԑRI-mediated basophil activation and degranulation, exhibiting superior IgE-neutralizing activity to that of omalizumab. UB-221 and ligelizumab bound cellular IgE and effectively neutralized IgE in sera of patients with atopic dermatitis with equal strength, while omalizumab lagged behind. A single UB-221 dose administered to cynomolgus macaques and human IgE (ε, κ)–knockin mice could induce rapid, pronounced serum-IgE reduction. A single UB-221 dose administered to patients with CSU in a first-in-human trial exhibited durable disease symptom relief in parallel with a rapid reduction in serum free-IgE level.

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Section: Ige Protein and Ige Mrna Expression In Pbmcs Treated With Ub...mentioning

confidence: 99%

IgE-neutralizing UB-221 mAb, distinct from omalizumab and ligelizumab, exhibits CD23-mediated IgE downregulation and relieves urticaria symptoms

Kuo¹,

Li²,

Chen³

et al. 2022

Journal of Clinical Investigation

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show abstract

“…Of note, ligelizumab initially showed significantly better symptom control over omalizumab in a phase2b clinical study for CSU however these results were not replicated in a larger Phase 3 setting. In addition, while omalizumab is approved for the treatment of asthma, ligelizumab did not significantly improve asthma control or exacerbation rates compared to omalizumab or placebo ( 76 ). Together findings from these two studies suggest that these mechanistic/binding differences are important in different disease settings.…”

Section: Anti-ige Therapymentioning

confidence: 99%

Biologics as novel therapeutics for the treatment of allergy: Challenges and opportunities

et al. 2022

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Over the last 4 decades there has been a significant global increase in the incidence and prevalence of IgE-mediated allergy. Although much progress has been made in the management of allergy via patient education, pharmacotherapy and immunomodulatory treatment regimens, significant unmet need remains. Advancements in our knowledge base surrounding the type 2 immune response, production of IgE and maintenance of immunological memory has led the field to explore targeted intervention of allergic pathways using monoclonal antibodies (mAbs). Intervention at various stages of the allergic cascade offers the opportunity to prevent initiation and/or maintenance of the type 2 immune response and effectively provide therapeutic benefit to patients. Furthermore, a better understanding of the protective mechanisms involved in allergen specific immunotherapy (AIT) has led us to appreciate the interplay of immunoglobulins in the allergic response, specifically the benefit in shifting the IgG:IgE ratio in favor of functionally relevant blocking IgG. Thus, treatments that lower IgE or boost IgG with the ability to outcompete IgE binding to allergen also present a favorable approach in the treatment of allergy. In this short review we discuss and highlight recent advances in the use of biologics to treat severe allergy, highlighting the key challenges but also the significant opportunities and advances to date.

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“…Owing to these properties, omalizumab is indicated for the treatment of moderate-to-severe asthma (116), allergic rhinitis (117), and chronic idiopathic/spontaneous urticaria (CIU/CSU) (118)(119)(120). However, a newer anti-IgE mAb ligelizumab (121) failed to show its efficacy in the treatment of severe asthma (122), while it was more effective than omalizumab in the treatment of CIU/CSU (123). It was speculated that the differential efficiencies of omalizumab and ligelizumab in inhibiting FcεRI and CD23 bindings may contribute to the difference in the efficacies on severe asthma, although it requires further investigation.…”

Section: Ige Ige Receptors and Omalizumabmentioning

confidence: 99%

Immunoglobulin E-Dependent Activation of Immune Cells in Rhinovirus-Induced Asthma Exacerbation

et al. 2022

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Acute exacerbation is the major cause of asthma morbidity, mortality, and health-care costs. Respiratory viral infections, particularly rhinovirus (RV) infections, are associated with the majority of asthma exacerbations. The risk for bronchoconstriction with RV is associated with allergic sensitization and type 2 airway inflammation. The efficacy of the humanized anti-IgE monoclonal antibody omalizumab in treating asthma and reducing the frequency and severity of RV-induced asthma exacerbation is well-known. Despite these clinical data, mechanistic details of omalizumab's effects on RV-induced asthma exacerbation have not been well-defined for years due to the lack of appropriate animal models. In this Perspective, we discuss potential IgE-dependent roles of mast cells and dendritic cells in asthma exacerbations.

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Ligelizumab treatment for severe asthma: learnings from the clinical development programme

Cited by 28 publications

References 32 publications

IgE-neutralizing UB-221 mAb, distinct from omalizumab and ligelizumab, exhibits CD23-mediated IgE downregulation and relieves urticaria symptoms

IgE-neutralizing UB-221 mAb, distinct from omalizumab and ligelizumab, exhibits CD23-mediated IgE downregulation and relieves urticaria symptoms

Biologics as novel therapeutics for the treatment of allergy: Challenges and opportunities

Immunoglobulin E-Dependent Activation of Immune Cells in Rhinovirus-Induced Asthma Exacerbation

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