IgE: The Key Therapeutic Target for Allergy Treatment

On October 20, 2025, RAPT Therapeutics announced positive results from the Phase II clinical trial of its long-acting IgE antibody, RPT904 (JYB1904), for the treatment of chronic spontaneous urticaria (CSU). RPT904 (JYB1904) was modified based on the approved drug Omalizumab, and has shown characteristics that are superior or equivalent to Omalizumab in terms of dosing frequency, efficacy, and safety, demonstrating Best-in-Class (BIC) potential. Driven by this positive news, RAPT Therapeutics' stock price rose by ~15% on that day.

RPT904 (JYB1904) was originally developed by Jeyou Pharma. In December 2024, RAPT Therapeutics announced the licensing of the global rights (excluding China) for JYB1904.

Source: RAPT Therapeutics Website

The human body has five types of immunoglobulins (Ig), including IgA, IgD, IgE, IgG, and IgM, each performing different immunological functions. Among them, IgE is the least abundant antibody in human serum, yet it can trigger strong allergic reactions in multiple tissues and organs [2], playing a core role in Type-I immediate hypersensitivity reactions. Multiple studies have shown that in allergic patients, antibody isotype switching may favor IgE in the nasal and bronchial mucosa and adjacent lymphoid tissues at sites of allergen contact [3]. IgE plays a critical role in the initiation and progression of allergic reactions, making it a key target for the allergy treatment.

Immunoglobulin E (IgE) is composed of two heavy chains and two light chains. The heavy chain contains one variable region and four constant regions (Cε1-Cε4). IgE-Fc adopts a bent, asymmetric conformation (driven by the Cε2–Cε3–Cε4 domain architecture) rather than a classic hinge as seen in IgG. The two Cε2 domains fold backward, contacting the Cε3 and Cε4 domains. Binding of IgE to a receptor induces a conformational change, which further increases the bending [3]. By binding to allergens through its Fab arms, IgE exerts its effector function by binding to two receptors, FcεRI and CD23 (FcεRII) via the Fc fragment.

Structure of IgE [3]

FcεRI is a high-affinity receptor (KD≈10-10 M). It is highly expressed on the surface of mast cells and basophils as an αβγ2 tetramer.  It also exists as an αγ2 trimer on the surface of human monocytes, peripheral blood dendritic cells (DCs), and eosinophils.  The Cε3 domain of IgE binds to the two extracellular domains of the FcεRI α chain. The intracellular sequences of both the β and γ chains contain immunoreceptor tyrosine-based activation motifs (ITAMs). The β chain can amplify downstream signals upon FcεRI activation. After binding to FcεRI on the surface of mast cells and basophils, the cells become sensitized. Upon re-exposure to the allergen, the allergen is recognized and bound by the IgE-FcεRI complex on the cell surface, triggering an intracellular signaling cascade that leads to the rapid degranulation of mast cells, releasing inflammatory mediators such as histamine and leukotrienes, thereby inducing allergic symptoms [4].

CD23 (FcεRII), on the other hand, is a low-affinity receptor (KD≈10-7 M). It is widely expressed on B cells, activated T cells, antigen-presenting cells (APCs), and intestinal and respiratory epithelial cells. IgE binds to the C-terminal C-type lectin-like "head" of CD23 through the Cε3/Cε4 domains. CD23 is initially expressed as a membrane protein (mCD23) and can later be cleaved at the stalk region by metalloproteinases like ADAM-10, generating soluble CD23 fragments (sCD23) [3]. sCD23 can promote IgE synthesis by co-binding with IgE and CD21, while the allergen-IgE complex inhibits IgE synthesis via co-binding with mCD23. Therefore, the interaction between IgE and mCD23/sCD23 plays a critical role in maintaining IgE homeostasis [5]

Structure of IgE receptors [4]

An allosteric mechanism exists within the IgE molecule: binding to FcεRI will inhibit the binding with CD23, and vice versa. When IgE binds to FcεRI, the Cε3 domain adopts an “open” state, causing the two Cε3 domains to move away from each other and changing the angle between them, which impairs CD23 binding at the Cε3/Cε4 interface. Whereas when IgE binds to CD23, the Cε3 domains will move closer together and impede FcεRI binding with IgE [6].

The allosteric effect of IgE [6]

IgE-targeted drugs are primarily monoclonal antibodies. Their core therapeutic mechanism is to block the binding of IgE to its receptors, thereby effectively inhibiting the release of allergic mediators (such as histamine). Omalizumab, developed by Novartis and Genentech, is the only approved IgE-targeted drug and has long dominated the market. Its binding epitope minimally overlaps with the FcεRIα binding epitope, and it primarily prevents IgE from binding to the FcεRIα receptor through steric hindrance. Furthermore, its binding site on IgE overlaps with that of CD23, exerting an inhibitory effect through direct competitive binding [7].

To prepare for the Omalizumab patent cliff, Novartis developed the next-generation monoclonal antibody, Ligelizumab. In vitro studies indicated that its binding affinity with IgE was approximately 88 times higher than Omalizumab [8]. However, Ligelizumab failed to demonstrate sufficient clinical advantage in multiple Phase III clinical trials for CSU and peanut allergy [9][10]. Based on these results, Novartis has officially terminated the clinical research of Ligelizumab for the treatment of CSU and food allergy.

The binding epitope of Omalizumab and Ligelizumab [8]

In contrast, positive developments continue to emerge in biotech companies. In addition to JYB1904 by Jeyou Pharma, LongBio Pharma also announced Phase II clinical data in March 2025 for its self-developed, long-acting anti-IgE antibody, LP-003, for the treatment of CSU. In a head-to-head comparison with Omalizumab, LP-003 achieved superior clinical efficacy and safety, demonstrating a significant therapeutic advantage [11]. Currently, LP-003 has successfully entered the Phase III clinical trial stage according to Jeyou. Based on the excellent Phase II clinical results, it is expected to become another highly potential anti-IgE monoclonal antibody drug, offering more treatment options for patients.

Selected Anti-IgE Drug

The positive news of the Anti-IgE mAb development brings new possibilities for allergy treatment. KACTUS is thrilled to offer our IgE product collection covering different domain forms such as Cε2-Cε3 and Cε2-Cε4 and spanning various species. KACTUS is dedicated to accelerating the drug development process for allergic diseases.

Product Validation Data

Immobilized Human Fc epsilon RI alpha, hFc Tag at 0.5 μg/ml (100 μl/well) on the plate. Dose response curve for Human IgE-Fc (Cε3-Cε4), His Tag with the EC50 of 1.5 ng/ml determined by ELISA (QC Test).

Immobilized Human Fc epsilon RI alpha, hFc Tag at 0.5 μg/ml (100 μl/well) on the plate. Dose response curve for Human IgE-Fc (Cε2-Cε4), His Tag with the EC50 of 2.5 ng/ml determined by ELISA (QC Test).

Immobilized Human Fc epsilon RI alpha, hFc Tag at 1 μg/ml (100 μl/well) on the plate. Dose response curve for Mouse IgE-Fc (Cε2-Cε4), His Tag with the EC50 of 3.1 ng/ml determined by ELISA (QC Test).

 

Product List

References:

[1] Events and Presentations | RAPT Therapeutics, Inc.

[2] Zellweger F, Eggel A. IgE-associated allergic disorders: recent advances in etiology, diagnosis, and treatment. Allergy. 2016 Dec;71(12):1652-1661. doi: 10.1111/all.13059. PMID: 27709638.

[3] Shamji MH, Valenta R, Jardetzky T, Verhasselt V, Durham SR, Würtzen PA, van Neerven RJJ. The role of allergen-specific IgE, IgG and IgA in allergic disease. Allergy. 2021 Dec;76(12):3627-3641. doi: 10.1111/all.14908. Epub 2021 Jun 8. PMID: 33999439; PMCID: PMC8601105.

[4] Novosad J, Krčmová I. Evolution of our view on the IgE molecule role in bronchial asthma and the clinical effect of its modulation by omalizumab: Where do we stand today? Int J Immunopathol Pharmacol. 2020 Jan-Dec;34:2058738420942386. doi: 10.1177/2058738420942386. PMID: 32689848; PMCID: PMC7375718.

[5] Gould HJ, Sutton BJ. IgE in allergy and asthma today. Nat Rev Immunol. 2008 Mar;8(3):205-17. doi: 10.1038/nri2273. PMID: 18301424.

[6] Sutton BJ, Davies AM, Bax HJ, Karagiannis SN. IgE Antibodies: From Structure to Function and Clinical Translation. Antibodies (Basel). 2019 Feb 22;8(1):19. doi: 10.3390/antib8010019. PMID: 31544825; PMCID: PMC6640697.

[7] Guntern P, Eggel A. Past, present, and future of anti-IgE biologics. Allergy. 2020 Oct;75(10):2491-2502. doi: 10.1111/all.14308. Epub 2020 Apr 21. PMID: 32249957; PMCID: PMC7541678.

[8] Wood RA, Chinthrajah RS, Eggel A, Bottoli I, Gautier A, Woisetschlaeger M, Tassinari P, Altman P. The rationale for development of ligelizumab in food allergy. World Allergy Organ J. 2022 Sep 13;15(9):100690. doi: 10.1016/j.waojou.2022.100690. PMID: 36185545; PMCID: PMC9483652.

[9] Novartis provides an update on Phase III ligelizumab (QGE031) studies in chronic spontaneous urticaria (CSU) | Novartis

[10] Efficacy and Safety of QGE031 (Ligelizumab) in Patients With Peanut Allergy | MedPath

[11] Breakthrough! Exciting interim Phase II Data of LP-003 in CSU released by Longbio at AAAAI 2025