Past, present, and future of anti‐IgE biologics

Abstract

The discovery of immunoglobulin E (IgE) in 1967 1-9 together with the identification of its central role in the pathogenesis of allergic inflammation (reviewed elsewhere 10-14) has set the stage for the development of therapeutic anti-IgE strategies (Box 1). The generation of detailed knowledge about the molecular and structural characteristics of IgE has further accelerated this process. IgE consists of two identical heavy and light chains. Each heavy chain includes four constant epsilon domains (Cε1-4). 15 Overall, the IgE antibody features high flexibility. Particularly, the IgE-Fc part has been described to undergo important conformational changes depending on its interaction partner. While IgE binding to the high-affinity receptor FcεRI on allergic effector cells induces an open Fc conformation, low affinity receptor FcεRII/CD23 binding on antigen-presenting cells (APC), airway epithelial cells (AEC) or B-cells forces IgE in a closed Fc conformation and thereby ensures mutually exclusive interaction with the two receptors. 16-18 In addition to the free form of IgE, B cells express membrane IgE (mIgE) that is part of the B-cell receptor (BCR) and contains an extracellular membrane-proximal domain (EMPD). 19-21 Identification of these features has been key for the development of efficient targeting strategies. Over the last decades, the field of anti-IgE biologicals has advanced into a competitive and active field of investigation. Different companies and research institutions are currently assessing approaches to specifically target IgE in pre-clinical studies or clinical trials (Table 1). 22,23 Here, we provide

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

“…Omalizumab, a humanized monoclonal antibody, was the only approved anti-IgE antibody on the market for clinical use till now. Since there are some limitations associated with omalizumab (28)(29)(30)(31), a lot of efforts have been made to develop alternative anti-IgE antibodies that could potentially overcome these challenges and lead to better clinical outcomes (31).…”

“…Over the last decades, several anti-IgE antibodies have been generated and assessed in pre-clinical studies or clinical trials (31,(42)(43)(44). To date, besides ligelizumab (QGE031) is still under active investigation in clinical trials, other antibodies have been discontinued due to strategic decisions or failure to achieve primary endpoints in clinical trials (31,43,45). Ligelizumab is a novel humanized monoclonal antibody with high affinity to IgE.…”

“…Ligelizumab is a novel humanized monoclonal antibody with high affinity to IgE. Because of different mechanistic and functional profile compared with omalizumab (45), ligelizumab lacked superior efficacy in phase II clinical trials with allergic asthma patients compared to omalizumab (31,45). Therefore, ligelizumab was given up for the treatment of allergic asthma and chosen for the treatment of chronic spontaneous urticaria (CSU).…”

“…Therefore, ligelizumab was given up for the treatment of allergic asthma and chosen for the treatment of chronic spontaneous urticaria (CSU). Based on the lessons learned from the previous studies (31,(42)(43)(44), it seems that too much emphasis has been placed on binding characteristics and the generation of novel mechanism of action different from omalizumab, and the less attention has been paid to fully understand or consider the exact mechanisms underlying omalizumab-dependent regulation of IgE production resulting in failure in clinical trials. Therefore, there certainly still exists a lot of challenges as well as room for improvement of anti-IgE biologicals.…”

“…Despite showing efficacy against allergic diseases, in particular against allergic asthma, omalizumab still has some limitations (28)(29)(30)(31). Firstly, there are two typical isomerization hotspots of aspartic acid-glycine (Asp-Gly) sequences at residues 32-33 in complementarity-determining regions (CDR) of light chain and at residues 55-56 in CDR of heavy chain, which resulted in chemical instability and lower affinity to IgE (28,29,32).…”