Allergic diseases are inflammatory disorders that involve many types of cells and factors, including allergens, immunoglobulin (Ig)E, mast cells, basophils, cytokines and soluble mediators. Among them, IgE plays a vital role in the development of acute allergic reactions and chronic inflammatory allergic diseases, making its control particularly important in the treatment of IgE-mediated allergic diseases. This review provides an overview of the current state of IgE targeted therapy development, focusing on three areas of translational research: IgE neutralization in blood; IgE-effector cell elimination; and IgE+ B cell reduction. IgE-targeted medicines such as FDA approved drug Xolair (Omalizumab) represent a promising avenue for treating IgE-mediated allergic diseases given the pernicious role of IgE in disease progression. Additionally, targeted therapy for IgE-mediated allergic diseases may be advanced through cellular treatments, including the modification of effector cells.
The mechanism of allergic diseases is complex. In clinical practice, allergic diseases could be divided into two categories: IgE mediated and non-IgE mediated. Allergic disorders are characterized by inflammatory responses involving many types of cells, including mast cells and basophils, and various biological molecules, including cytokines (e.g. interleukin 4) and soluble mediators (e.g. histamine) . IgE, an antibody class found only in mammals, has unique properties and plays a central role in IgE-mediated allergic diseases. Typically, it is the least abundant Ig isotype, with a concentration of about 150 ng/ml, compared with 10 mg/ml for IgG in the circulation of healthy individuals . The half-life of IgE in serum is about 3 days, compared with 20 days for IgG, but its lifespan can be extended to 2 weeks in skin tissue . Specific IgEs are upregulated in response to exposure to specific allergens. There are two types of IgE molecules: free IgE produced by plasma cells and membrane-bound IgE maintained on the surface membranes of B cells through class switching .
IgE plays a key role in mediating the initiation and development of allergic diseases. The IgE molecule performs its biological function by binding its receptors on target cells, activating the induction immunomodulatory and protecting against parasitic worms (helminths) and the expulsion of environmental substances that include toxins, venoms, irritants and xenobiotics . When the body encounters an allergen for the first time, IgM molecules in B cells are converted by class switching to IgE molecules . Then, specific B cells initiate an IgE response, during which IgE+ B cells start to secrete free IgE into the blood where it can bind the high-affinity IgE receptor FcεR I on mast cells or basophils . This response sensitizes the organism so that when itre-encounters the allergen, the allergen molecules are bound by specific IgE molecules on the surface of mast cells, causing them to undergo degranulation and to synthesize and release large quantities of allergic mediators (i.e., histamine, leukotriene, and platelet-activating factor), which then produce a local or systemic allergic reaction . Apart from binding FcεRI on mast cells and basophils, IgE can also bind its low-affinity receptor FcεRII, which is expressed by B cells and monocytes . Surface receptors on B cells enable them to take in bound allergens, process them, and present them to T cells, priming subsequent targeted innate immunity responses to the allergen in the future . Anti-IgE therapy can reduce IgE receptor expression on effector cells; because IgE is a positive regulator of both FcεRI and FcεRII, reduced IgE results in reduced IgE receptor expression as well [20, 21]. With co-stimulation of CD79A (Ig-α) and CD79B (Ig-β), membrane-anchored IgE can also trigger the proliferation and differentiation of B cells .
There is great interest in the development of new drugs or methods that would alleviate allergic diseases by affecting molecular IgE activities in a manner that is safe, effective, and convenient (Table 1).
IgE is an important target for allergic disease therapy. The main method of IgE neutralization being pursued involves achieving specific binding and neutralization of free IgE in serum to prevent it from binding receptors on target cells, thereby inhibiting allergen-induced early/late allergic reactions (Fig. 1).
Scheme of anti-IgE therapy strategies for IgE-mediated allergic diseases. Through immunoadsorption, free IgEs in serum can be bound specifically and neutralized, thereby preventing IgE association with IgE receptors on target cells and thus suppressing early/late allergy reactions. CTLA4Fcε, and similar agents, suppress the emergence of allergic reactions by reducing the number of effector cells, and hence the quantity of allergic mediators. Immunological drugs, like quilizumab, alleviate allergies by suppressing IgE+ B cells and controlling IgE generation
Immunoadsorption (IA), also called immune apheresis, has been adopted as an effective treatment for autoantibody-mediated diseases . IA utilizes plasmapheresis to remove immunoglobulin and immune complexes and in cytapheresis, immune cells from the circulation . Accordingly, IA could be successfully applied in patients with severe atopic dermatitis and high total serum IgE levels [24,25,26,27]. An IgE-specific adsorber, called IgEnio, has been developed . The pilot study indicates that IgEnio may be used to treat pollen-induce allergic asthma .
Ligelizumab, also developed by Novartis, is a humanized IgG1 monoclonal antibodytargeting the Cε3 region of IgE . Like omalizumab, ligelizumab inhibits the binding of free IgE to mast cells and basophils, thereby blocking the allergic reaction cascade and yielding clinical benefits to patients suffering from IgE-mediated allergic diseases.
Celastrol is bioactive compound extracted from Tripterygium wilfordii (Thunder god vine) that can induce T cells apoptosis . Thus, targeting celastrol specifically to mast cells in a manner that also reduces its toxicity is an attractive potential avenue for allergic disease treatment. This approach has been pursued by cross-linking celastrol with anti-FcεRI Fab, which has been shown to induce mast cell apoptosis, eliminating with them their pro-inflammatory factor cargo, and to limit celastrol toxicity . Treatment of allergic asthma model mice with anti-FcεRIα Fab-conjugated polymeric micelles was shown to reduce secretion of inflammatory factors and eosinophil infiltration rapidly and to lead to remission of symptoms of ovalbumin-induced allergic inflammation symptoms . The ability of anti-FcεRIα Fab-conjugated celastrol-loaded polymeric micelles to both block IgE binding of mast cells and induce mast cell apoptosis makes it a very attractive medicine for type I allergic diseases as well as for other mast cell-related diseases.
A phase II clinical trial showed that quilizumab is an effective candidate for treating allergic diseases safely and with high specificity . Quilizumab was shown to lower total IgE and specific IgE levels in the serum of patients with asthma, and this effect lasted for 6 months . It is hoped that quilizumab will be useful for the treatment and prevention of some IgE-mediated diseases, especially those for which there are no current medicines available . However, quilizumab treatment did not produce a clinically meaningful benefit in allergic asthma patients inadequately controlled by standard therapy, despite its high ability in reducing serum IgE levels and the good tolerability profile .
There are several types of IgE+ B cells, including plasma blasts, plasma cells, and IgE+ memory B cells . The earliest experiment aimed at eliminating IgE+ B cells specifically sought to modify T-cell receptors in combination with anti-IgE monoclonal antibody activity . The bsc-IgE/CD3 antibody is an artificially modified targeting antibody specific for both IgE and CD3. It binds specifically to cells that express membrane-bound IgE and can re-direct the cytotoxicity of prestimulated human T cells toward IgE+ B cells, at least in vitro, without causing degranulation of mast cells or release of free IgE. Bsc-IgE/CD3 is an antibody that could eliminate both IgE+ B cells and free IgE in serum . Therefore, bsc-IgE/CD3 is a new class candidate medicine for IgE-mediated allergic diseases.
FcγRIIβ is involved in B-cell homeostasis and FcγRIIβ abnormalities lead to autoimmune diseases . A novel antibody known as XmAb7195 was produced by humanization, affinity maturation, and Fc engineering using a murine anti-IgE antibody as template . XmAb7195 can isolate free IgE in serum, forming immune complexes with FcγRIIβ and IgE receptors on B cells that impede the formation of IgE+ B cells and reduce free and total IgE levels without affecting the antigen isotypes of other B cells . Because it has the added ability of binding FcγRIIβ, XmAb7195 can inhibit IgE+ B cell differentiation, thereby reducing the number of IgE secreting plasma cells . This reliable double mechanism can be utilized to reduce total IgE levels, while the remaining free IgE can be targeted continuously and effectively. A phase I clinical trial (NCT02148744) showed that XmAb7195 is more efficient at reducing IgE activity than omalizumab .
As so far, Omalizumab is the only FDA-approved recombinant humanized monoclonal antibody that neutralizes IgE to treat allergic diseases . Its use is supported by a large number of clinical trials demonstrating its effectiveness . Other IgE-neutralizing antibodies are being developed with the goal of more effectiveness and less side effects. Medicines that target IgE effector cells and IgE+ B cells are also in development. Apart from targeting medicines, cellular treatments are also being developed. For example, T cells may be mo