Introduction to Immunoglobulin E And Its Future Research Directions

Immunoglobulin E (IgE) is an antibody—a protein produced by the immune system in response to a possible invader. It is primarily involved in the allergic response but also fights infections from parasites.

IgE is a Y-shaped protein, made of two light chains and two heavy chains of peptides (building blocks of protein). The heavy chains form the body and arms of the Y shape, and the light chains attach just to the arms of the Y shape. IgE binds to two types of receptors—high-affinity receptors and low-affinity receptors. The binding sets off a chain reaction that causes the cells to release chemical immune mediators, which are responsible for the symptoms of an allergic reaction, and it also triggers different effects in cells. For example, when IgE binds to a specific marker on B cells, it inhibits the synthesis of more IgE. This is called negative feedback and is how the immune system regulates itself.

The discovery of IgE in 1967 together with the identification of its central role in the pathogenesis of allergic inflammation has set the stage for the development of therapeutic anti-IgE strategies. The generation of detailed knowledge about the molecular and structural characteristics of IgE has further accelerated this process.

The first therapeutic anti-IgE antibody is rhuMAb-E25—today best known as omalizumab (Xolair®)—approved in 2003. This drug for subcutaneous use is an injectable prescription medicine used to treat moderate to severe persistent asthma in people 6 years of age and older, nasal polyps in people 18 years of age and older, hronic spontaneous urticaria (CSU) in people 12 years of age and older.

Monoclonal antibody solutions have so far dominated the anti-IgE biologicals industry, and several organizations have successfully advanced their anti-IgE prospects to the level of clinical trials. However, in the past 20 years, none of these have received therapeutic application approval.

Pre-clinical studies are now evaluating a number of innovative anti-IgE approaches based on the knowledge gained from earlier anti-IgE research. These next-generation anti-IgE variations aim to be either more specific than the conventional anti-IgE antibody approaches or to have multifunctionality, and some of them depart from the conventional monoclonal antibody framework.

To achieve the highest level of therapy performance, future anti-IgE biologicals would focus on aspects of targeting the involved pathomechanisms. Therefore, in addition to neutralizing free IgE, an ideal IgE inhibitor should actively disrupt IgE:Fc RI complexes on allergic effector cells and reduce the synthesis of IgE in B cells by binding to either mIgE, CD23-bound IgE, or inhibitory co-receptors. The development of several candidates has marked the beginning of multi-level targeting.

However, as clinical trials have demonstrated, there is still much room for improvement of such approaches. While recent studies clearly suggest that more tailored anti-IgE approaches for different indications are required, the question whether a universal anti-IgE biological that shows high treatment efficacy in a multitude of allergic disorders could be developed by broadening the activity profile and following a multi-level IgE targeting strategy remains to be investigated.

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