Anti-IgE for the Treatment of Chronic Urticaria

Abstract

Urticaria and angioedema are very common. Management of chronic urticaria subtypes, which usually persist for many years, is challenging. Recent years have demonstrated that targeting IgE with antibodies provides a safe and efficient treatment approach. Whilst several anti-IgE antibodies have been developed, omalizumab is currently the only one approved for use. International and national guidelines recommend its use after failure of antihistamines at standard and increased dose. Whilst not yet approved, many new anti-IgE approaches are currently being investigated in pre-clinical studies or clinical trials. This non-systematic focused review summarizes current knowledge of omalizumab and other anti-IgE biologics in chronic urticaria using data extracted from PubMed, Google Scholar and clinical trial databases, clinicaltrials.gov and clinicaltrials.eu. For adults, there is good evidence from randomized clinical trials and real-world data that symptomatic treatment with omalizumab is efficacious and safe in chronic spontaneous urticaria (CSU), whereas evidence in chronic inducible urticaria (CINDU) and special populations is limited. Easy-to-use tools to identify non-responders and predict the required duration of treatment have not been established yet. Phase 2 b results of ligelizumab have not only demonstrated efficacy and safety but also superiority to omalizumab. Indeed, there is preliminary evidence that omalizumab non- or partial responders benefit from ligelizumab. Whereas further development of quilizumab was discontinued, other approaches, eg UB-221 or DARPins are under investigation. Anti-IgE treatment with omalizumab represents a landmark in the treatment of chronic urticaria, with and without angioedema, and there is light on the horizon suggesting success may come with various next-generation anti-IgE approaches.

Keywords: UB-221; anti-IgE therapy; ligelizumab; monoclonal antibody; omalizumab; quilizumab; urticaria.

Figure 1

Mechanisms of mast cell activation in chronic spontaneous urticaria. Type I autoimmunity is characterized by diverse antigens such as thyroperoxidase (TPO) crosslinking IgE autoantibodies. Type IIb autoimmunity is based on IgG autoantibodies against IgE or FcԑRI. Both autoimmune mechanisms lead to a degranulation of mast cells.

Figure 2

History and future of selected anti-IgE drugs for the treatment of chronic spontaneous urticaria. In 2003, omalizumab was approved by the FDA for the treatment of adults and adolescents aged 12 years and above with moderate to severe persistent allergic asthma whose symptoms are poorly controlled with inhaled corticosteroids. Approval by EMA followed in 2005. In 2014, omalizumab was the first treatment approved by FDA and EMA for chronic spontaneous urticaria. Whereas further development of quilizumab in chronic spontaneous urticaria was discontinued, in 2014, first results of ligelizumab and UB-221 were described. Both are promising candidates for a possible therapy of chronic spontaneous urticaria in the future.

Figure 3

Mechanisms of various currently approved or in trials investigated drugs for chronic spontaneous urticaria. Anti-IgE drugs omalizumab, ligelizumab and UB-221 bind to free IgE and, therefore, induce a downregulation of FcԑRI. For omalizumab, an acceleration of the dissociation of IgE from FcεRI was shown. There are hints that omalizumab reduces the production of IgE. Quilizumab binds to the M1-prime segment of membrane-expressed IgE inducing a depletion of IgE-switched and memory B cells.