P11 Identification of IgE-reactive haptens for prevention of severe allergic reactions

Abstract

HDM is one of the most important allergen sources worldwide. HDM allergy is a major risk factor for the development of allergic asthma which is one of the most severe manifestations of allergy. Der p 1, Der p 2, Der p 23, are the major HDM allergens which are recognized by 80-90% of HDM-allergic patients. Sensitization of Der p 1, Der p 2 and Der p 23 are strongly associated with asthma. Allergen-specific therapy approaches are needed for treatment and prevention of HDM-induced asthma. 

In this project, we aim to explore the feasibility of an allergen-specific approach for the treatment of HDM allergy which is based on IgE-reactive haptens derived from the major HDM allergens. IgE-reactive haptens are small peptides mimicking the IgE binding site of one or few IgE antibodies which accordingly have no or a strongly reduced ability to cross-link effector cells that are armed with IgE antibodies directed against several different epitopes on the allergen as compared to the complete allergen. The goal of this project is to create IgE-reactive haptens which resemble the major IgE binding sites of the major HDM allergens to saturate effector cell-bound HDM-specific IgE without inducing allergic reactions so that subsequent binding of the full allergen is blocked. IgE-reactive haptens are therefore considered as a passive treatment approach especially for topical treatement.

The feasibility of the treatment approach based on IgE-reactive haptens will be evaluated first for Der p 23 for which a sequential epitope has been identified. The allergenic activity of this peptide versus the full allergen will be compared and, if necessary, the size of the peptide will be further reduced and modifications will be made to prevent aggregation. Through this procedure IgE-reactive haptens for Der p 23 will be obtained. For Der p 1 and Der p 2 random fragment libraries will be constructed in phage lambda gt11 and screened with IgE antibodies from HDM allergic patients to identify haptenic peptides. As another approach for obtaining IgE-reactive haptens we will search in random peptide phage display libraries for binders to HDM allergen-specific IgE antibodies. For this purpose, IgE-reactive mimotopes will be bio-panned using HDM allergen-specific IgE. Allergenic activity of potentially haptenic peptides selected in the aforementioned approaches will be assessed by using rat basophilic leukemia (RBL-2H3) cells expressing huFcεRIα (huRBL cells), which will be sensitized with IgE antibodies from HDM-allergic patients. Furthermore, IgE-reactive and non-IgE-cross-linking haptens will be embedded into monomeric protein scaffolds and again evaluated for allergenic activity by basophil activation testing. Especially the ability of the haptenic structures to prevent effector cell degranulation upon subsequent exposure to HDM allergens will be evaluated.

This project will pave the road towards the new allergen-specific therapeutic approach for allergy through hapten-based passive saturation of effector cell-bound IgE preventing effector cell activation by subsequent exposure to HDM allergens. This new treatment approach could be implemented through topical application, allowing for the alleviation of symptoms locally. It may offer an efficient treatment to achieve protection and prevent asthma exacerbation caused by exposure to HDM allergens.

Prinicipal Investigator