The rationale for development of ligelizumab in food allergy.

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.

Identification and mechanistic characterization of low-molecular-weight inhibitors for HuR.

Careful regulation of mRNA half-lives is a fundamental mechanism allowing cells to quickly respond to changing environmental conditions. The mRNA-binding Hu proteins are important for stabilization of short-lived mRNAs. Here we describe the identification and mechanistic characterization of the first low-molecular-weight inhibitors for Hu protein R (HuR) from microbial broths (Actinomyces sp.): dehydromutactin (1), MS-444 (2) and okicenone (3). These compounds interfere with HuR RNA binding, HuR trafficking, cytokine expression and T-cell activation. A mathematical and experimental analysis of the compounds' mode of action suggests that HuR homodimerizes before RNA binding and that the compounds interfere with the formation of HuR dimers. Our results demonstrate the chemical drugability of HuR; to our knowledge HuR is the first example of a drugable protein within the Hu family. MS-444, dehydromutactin and okicenone may become valuable tools for studying HuR function. An assessment of HuR inhibition as a central node in malignant processes might open up new conceptual routes toward combatting cancer.