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IgE Antibodies: From Structure to Function and Clinical Translation

1
King’s College London, Randall Centre for Cell and Molecular Biophysics, London SE1 1UL, UK
2
Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK
3
King’s College London, St John’s Institute of Dermatology, London SE1 9RT, UK
*
Authors to whom correspondence should be addressed.
Antibodies 2019, 8(1), 19; https://doi.org/10.3390/antib8010019
Received: 5 January 2019 / Revised: 11 February 2019 / Accepted: 15 February 2019 / Published: 22 February 2019
(This article belongs to the Special Issue Structure and Function of Antibodies)
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PDF [19173 KB, uploaded 22 February 2019]
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Abstract

Immunoglobulin E (IgE) antibodies are well known for their role in mediating allergic reactions, and their powerful effector functions activated through binding to Fc receptors FcεRI and FcεRII/CD23. Structural studies of IgE-Fc alone, and when bound to these receptors, surprisingly revealed not only an acutely bent Fc conformation, but also subtle allosteric communication between the two distant receptor-binding sites. The ability of IgE-Fc to undergo more extreme conformational changes emerged from structures of complexes with anti-IgE antibodies, including omalizumab, in clinical use for allergic disease; flexibility is clearly critical for IgE function, but may also be exploited by allosteric interference to inhibit IgE activity for therapeutic benefit. In contrast, the power of IgE may be harnessed to target cancer. Efforts to improve the effector functions of therapeutic antibodies for cancer have almost exclusively focussed on IgG1 and IgG4 subclasses, but IgE offers an extremely high affinity for FcεRI receptors on immune effector cells known to infiltrate solid tumours. Furthermore, while tumour-resident inhibitory Fc receptors can modulate the effector functions of IgG antibodies, no inhibitory IgE Fc receptors are known to exist. The development of tumour antigen-specific IgE antibodies may therefore provide an improved immune functional profile and enhanced anti-cancer efficacy. We describe proof-of-concept studies of IgE immunotherapies against solid tumours, including a range of in vitro and in vivo evaluations of efficacy and mechanisms of action, as well as ex vivo and in vivo safety studies. The first anti-cancer IgE antibody, MOv18, the clinical translation of which we discuss herein, has now reached clinical testing, offering great potential to direct this novel therapeutic modality against many other tumour-specific antigens. This review highlights how our understanding of IgE structure and function underpins these exciting clinical developments. View Full-Text
Keywords: Immunoglobulin E; FcεRI; CD23; allostery; cancer immunotherapy; AllergoOncology; IgE effector functions; monocytes; macrophages; ADCC Immunoglobulin E; FcεRI; CD23; allostery; cancer immunotherapy; AllergoOncology; IgE effector functions; monocytes; macrophages; ADCC
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Sutton, B.J.; Davies, A.M.; Bax, H.J.; Karagiannis, S.N. IgE Antibodies: From Structure to Function and Clinical Translation. Antibodies 2019, 8, 19.

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