Therapeutic antibodies for birch pollen-related food allergy

More than 70% of birch pollen-allergic individuals develop allergic reactions to certain foods, most often to apple. The clinical symptoms are confined to the oral cavity and summarized in the term oral allergy syndrome. This birch pollen-related apple allergy is the most abundant food allergy in adolescents and adult individuals and also affects children. Unfortunately, the therapeutic efficacy of immunotherapy with birch pollen on the associated apple allergy is limited. Therefore, we aim at the development of a combined treatment for birch pollen and birch pollen-related food allergy. Our previously performed FWF-funded clinical study KLI96 revealed that sublingual administration of the recombinant major apple allergen Mal d 1 significantly reduces apple-induced allergic reactions in birch pollen-allergic individuals. So far, our experimental results indicate that Mal d 1-specific antibodies contribute to the therapeutic success because they prevent IgE-binding to the apple allergen. In the present project the biophysical and immunological characteristics of these so-called blocking Mal d 1-specific antibodies shall be elucidated. For this purpose, we will produce recombinant antibodies to determine their sites of recognition (epitopes) on Mal d 1. These insights will help to produce recombinant variants of the allergen that upon administration to allergic individuals will induce the production of blocking antibodies (active immunotherapy). Furthermore, recombinant antibodies that concomitantly reduce allergic reactions to birch pollen and apple can be directly administered to allergic individuals (passive immunotherapy). In summary, this project aims in the development of two complementary approaches for the concomitant treatment of birch pollen and birch pollen-related food allergy. The immunological insights gained from this study will help to elucidate the immune mechanisms relevant for successful allergy treatment and also contribute to develop therapeutic approaches for other disorders that result from immunological cross-reactivity.

Allergies affect more than 25% of the population worldwide. This overreaction of the immune system to allergens, e.g. in pollen or house dust mites, causes symptoms such as hayfever and allergic asthma. Allergies are mediated through the formation of allergen-specific immunoglobulin E (IgE) antibodies that activate effector cells such as mast cells and basophils to release mediators, e.g. histamine. Allergen immunotherapy is the treatment of choice to achieve a long-term reduction of allergic symptoms. It consists of a continuous stimulation of the immune system with well-defined amounts of the allergen over a long period of time. One working mechanism of allergen immunotherapy is the production of so-called blocking antibodies. These antibodies bind to the allergens and thereby prevent the induction of IgE-mediated allergic symptoms. Despite their relevance for therapeutic success, the features of antibodies that make them successful blocking antibodies are still not fully understood. This project aimed to elucidate some characteristics of functional IgE-blocking antibodies. This knowledge is relevant for an improved allergy treatment in the future. We engineered recombinant allergen-specific monoclonal antibodies from immune cells in peripheral blood of successfully treated allergic individuals. These antibodies served as standardized tools to link selected features with blocking bioactivity. We could demonstrate that IgE-blocking activity correlates positively with their binding force to the allergen. Moreover, the monoclonal antibodies served to establish different experimental protocols for subsequent analysis of the complex polyclonal antibodies in the sera of treated individuals. We learnt that in contrast to the assumption that blocking antibodies are IgG4 antibodies, IgG1 antibodies were more important for blocking in the early phase of the therapy. These insights are important for future endeavours to define biomarkers indicating the success of allergen immunotherapy. Finally, we could demonstrate that the therapy with a reference allergen only induces blocking antibodies to related allergens if their molecular identity is very high. This finding explains why immunotherapy with one reference allergen is not always successful in the reduction of so-called cross-reactive allergies, e.g. apple allergy of birch pollen-allergic individuals. In summary, our insights contribute to a better understanding of how effective allergen immunotherapy works. These insights will help to improve the strategies for more efficient treatment of allergies and cross-reactive allergies.