Recombinant Allergens for Pollen Immunotherapy

Michael Wallner; Ulrike Pichler; Fatima Ferreira

Disclosures

Immunotherapy. 2013;5(12):1323-1338. 

In This Article

Abstract and Introduction

Abstract

Specific immunotherapy (IT) represents the only potentially curative therapeutic intervention of allergic diseases capable of suppressing allergy-associated symptoms not only during treatment, but also after its cessation. Presently, IT is performed with allergen extracts, which represent a heterogeneous mixture of allergenic, as well as nonallergenic, compounds of a given allergen source. To overcome many of the problems associated with extract-based IT, strategies based on the use of recombinant allergens or derivatives thereof have been developed. This review focuses on recombinant technologies to produce allergy therapeuticals, especially for allergies caused by tree, grass and weed pollen, as they are among the most prevalent allergic disorders affecting the population of industrialized societies. The reduction of IgE-binding of recombinant allergen derivatives appears to be mandatory to increase the safety profile of vaccine candidates. Moreover, increased immunogenicity is expected to reduce the dosage regimes of the presently cumbersome treatment. In this regard, it has been convincingly demonstrated in animal models that hypoallergenic molecules can be engineered to harbor inherent antiallergenic immunologic properties. Thus, strategies to modulate the allergenic and immunogenic properties of recombinant allergens will be discussed in detail. In recent years, several successful clinical studies using recombinant wild-type or hypoallergens as active ingredients have been published and, currently, novel treatment forms with higher safety and efficacy profiles are under investigation in clinical trials. These recent developments are summarized and discussed.

Introduction

At present, allergen-specific immunotherapy (IT) represents the only disease-modifying treatment for allergic diseases. However, the treatment strategy is highly dependent on the quality of the allergen product applied. Allergen extracts have been developed as active ingredients for this therapeutic intervention, yet due to their biologic origin, the molecular composition of such products can vary considerably. Given the fact that the most important allergen sources harbor more than a single allergen, it is technically tremendously challenging for allergen manufacturers to define the exact potency of their extracts. Practically, either total IgE binding of the extract or IgE binding to a very limited number of major allergens can be quantified. On the other hand, recombinant technology can provide the means to overcome such problems. Starting with the cloning of the first allergens in 1988, the production of allergenic molecules in heterologous expression systems has become a routine procedure.[1–3] The main advantages of recombinant allergens are that the molecules can be fully characterized and produced with a high batch-to-batch consistency, the reagents can be easily quantified allowing definition of the accurate potency of a therapeutic product, and the proteins can be formulated according to the need of the patients. In other words, recombinant technology allows the production of low IgE-binding allergens with a high T cell-activating and -modulating capacity, thus leading to an improved safety and efficacy profile of allergy vaccines.[4] Moreover, the formulations contain only the relevant components, which is impossible to accomplish with allergen extracts, thus de novo sensitizations to other allergens, as observed in extract IT, can be excluded by careful patient selection.[5,6] Multiple sensitizations towards several allergens could in principle hinder the routine application of recombinants for therapy; however, as elegantly demonstrated for grass pollen IT, combinations of several recombinant allergens in a single vaccine preparation can be clinically effective.[7]

This review will discuss concepts to generate IT vaccine candidates for tree, grass and weed pollen allergies. Candidate molecules demonstrating improved safety and efficacy profiles have been developed for many allergen sources and are in the pipeline for clinical testing (summarized in Table 1). For birch and grass pollen, the first successful clinical trials based on recombinant allergens could deliver encouraging results for further developments. Therefore, an optimistic view towards allergy vaccines based on recombinant technology is well supported and the first clinical products could be marketable within the next few years.

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