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.
Highlights
Immunoglobulin E (IgE), named in 1968 [1,2,3], was the last of the five classes of human antibodies to be discovered, and today is commonly associated with the various manifestations of allergic disease [4]
FcεRI is expressed on tissue mast cells, blood basophils, airway epithelial and smooth muscle cells, intestinal epithelial cells, and various antigen-presenting cells (APCs), monocytes and macrophages [7,8,9,10,11]; the cross-linking of receptor-bound allergen-specific IgE on mast cells and basophils by allergen is the signal for cell degranulation, the release of pre-formed mediators of inflammation and an immediate hypersensitivity response that can be powerful enough to cause anaphylactic shock and even death
Anti-IgE antibodies of the IgG class, such as aεFab, directed against the Fc region clearly have potential as anti-allergy therapeutics if, by either steric or allosteric means, they inhibit FcεRI or CD23 engagement
Summary
Immunoglobulin E (IgE), named in 1968 [1,2,3], was the last of the five classes of human antibodies to be discovered, and today is commonly associated with the various manifestations of allergic disease [4]. When we put these structural data together to build models of the whole IgE molecule, it is clear that there are constraints upon the disposition of the Fab arms when the Fc is receptor bound, and there may be restrictions upon the receptor-binding capability of the Fc region when IgE engages target antigens; we lack high-resolution structural data on the complete IgE molecule Appreciation of these constraints and the consequences of the flexibility and dynamics of the IgE molecule as a whole, are clearly important for engineering an IgE molecule for immunotherapy that combines the desired antigen-binding and receptor-mediated activities
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