The rationale for development of ligelizumab in food allergy

Abstract

Food allergy (FA) is a growing healthcare problem worldwide and the rising prevalence in many countries can be attributed to lifestyle, environmental, and nutritional changes. Immunoglobulin E (IgE)-mediated FA is the most common form of FA affecting approximately 3%-10% of adults and 8% of children across the globe. Food allergen-induced immediate hypersensitivity reactions mediated by IgE and high-affinity IgE receptor (FcεRI) complexes on mast cells and basophils are a major hallmark of the disease. FA can affect several aspects of health-related quality of life and impose a substantial financial burden on patients and healthcare systems. Although currently there is one United States Food and Drug Administration (FDA) and European Medicines Agency (EMA)-approved treatment for peanut allergy (Palforzia), the main treatment approaches are based on allergen avoidance and symptom management. Thus, there is an urgent need for more effective and ideally disease-modifying strategies. Given the crucial role of IgE in FA, anti-IgE monoclonal antibodies are considered promising therapeutic agents. Talizumab was the first humanized anti-IgE antibody to demonstrate substantial protection against allergic reactions from accidental peanut exposure by substantially increasing the peanut reactivity threshold on oral food challenge. However, development of talizumab was discontinued and further trials were performed using omalizumab. In double-blind, Phase 2, placebo-controlled trials in patients with multi-FAs, sustained dosing with omalizumab, or omalizumab in combination with oral immunotherapy, enabled rapid desensitization to multiple trigger foods. In this review, we describe the development of ligelizumab (a derivative of talizumab), a next generation, humanized monoclonal anti-IgE antibody, its existing clinical evidence, and its potential in the management of FA. When compared with omalizumab, ligelizumab binds with ∼88-fold higher affinity for human IgE and recognizes a different epitope that substantially overlaps with the binding site of FcεRI. These properties translate into a high potency to block IgE/FcεRI signaling in both in vitro and in vivo studies. Given its efficient suppression of IgE levels, good safety and pharmacokinetic/pharmacodynamic profile, ligelizumab clearly warrants further studies for the potential management of FA.

Keywords: Food allergy; IgE; Ligelizumab; Omalizumab; Talizumab.

Fig. 1

Key pathogenic aspects of IgE-mediated food allergy, After food intake, food proteins are processed by antigen presenting cells of the gut and presented to the naïve CD4 T cells. These CD4 T cells differentiate into Th2 cells and produce type-2 cytokines (IL-4, IL-5, IL-9, and IL-13), promoting the differentiation of B cells into IgE-producing plasma cells. Re-exposure to food allergen leads to cross-linking of allergen-specific IgE bound to FcεRI on mast cells, inducing degranulation and release of several allergic mediators., FcεRI, high-affinity IgE receptor; gE, immunoglobulin E; IL, interleukin; PAF, platelet-activating factor

Fig. 2

Binding sites of omalizumab and ligelizumab on IgE: The two anti-IgE antibodies recognize similar but distinct epitopes on IgE. The ligelizumab epitope significantly overlaps with the binding site of FcεRI receptor and has only minor overlap with the CD23 receptor. The epitope of omalizumab is located more closely to the binding site of CD23. Consequently, ligelizumab more potently inhibits IgE binding to FcεRI than omalizumab, whereas omalizumab blocks IgE binding to CD23 more potently than ligelizumab.,^, FcεRI, high-affinity IgE receptor; FcεRII/CD23, low-affinity IgE receptor; IgE, immunoglobulin E

Fig. 3

Consequences of ligelizumab-mediated IgE binding blockade to FcεRI and CD23 expressing cells. Ligelizumab binds to free IgE and blocks its binding to FcεRI expressed on mast cells and basophils. The reduced availability of free IgE leads to the loss of FcεRI receptor numbers, which contributes to the effects of ligelizumab. The combined effects lead to a reduction in allergen-induced activation of mast cells and basophils, thereby reducing the release of pro-inflammatory mediators, with the potential to prevent food-induced allergic response and anaphylaxis. Ligelizumab also blocks the IgE/CD23 pathway, which may have implications for antigen presentation and IgE transport.,^, GI, gastrointestinal tract; FA, food allergy, FcεRI, high-affinity IgE receptor; CD23, low-affinity IgE receptor; IgE, immunoglobulin E