Recombinant Allergens for Pollen Immunotherapy
Recombinant Allergens for Pollen Immunotherapy
In recent years, several clinical studies using recombinant allergens or their derivatives have been published (summarized in Table 2). In general, the complexity of allergen extracts can hamper the development of allergy vaccines based on recombinant proteins. Nevertheless, as discussed in the previous chapters, a multitude of novel concepts engaging this problem have been developed and some have already been tested in clinical trials. The use of recombinant wild-type allergens in IT of grass and birch pollen allergy has proven to be clinically effective. A randomized, double-blind, placebo-controlled trial with 62 subjects performed by Jutel et al. used a combination of five different recombinant grass pollen allergens, including Phl p 1 and Phl p 2, two isoforms of Phl p 5, and Phl p 6 in approximately equimolar concentration. Active treatment, which was performed over a period of 1.5 years, led to the induction of grass pollen-specific IgG1 and IgG4 antibodies, in parallel with a suppression of specific IgE. Moreover, symptom and combined symptom medication scores were significantly improved, and the authors found significant improvement in five of seven separate categories in a rhinitis quality-of-life questionnaire. Adverse events reported in the actively treated group referred, in most cases, to local reactions at the injection site; however, severe systemic reactions, including urticaria, dyspnea and asthma exacerbation, were also reported. Later, a double-blind, placebo-controlled, dose-ranging safety trial using the same cocktail of recombinant grass pollen allergens was conducted. A total of 50 patients were divided into five groups (four active, one placebo) and actively treated groups received either 20, 40, 80 or 120 µg antigen as maximal dose following updosing, which started at 0.156 µg. In total, 13 injections were administered. Adverse systemic side effects grade I and II were reported in eight actively treated subjects, however, the reactions were evenly distributed within the groups. Conjunctival provocation tests were performed to assess treatment efficacy. Interestingly, the group treated with maximal 40 µg antigen showed the best improvement rates in this assay. Active treatment induced IgG1 and IgG4 antibodies against grass pollen, but there was quite some variation between the groups, which made it difficult to interpret the results. Moreover, active treatment had beneficial effects on late-phase reactions as determined by intracutaneous testing. A criticism of the study could be the small sample size. Nevertheless, even high final doses of recombinant allergens did not result in severe side effects, thus encouraging larger follow-up trials. For some allergen sources, such as birch pollen or cat hair, the use of a single disease-dominating allergen might be sufficient for IT. In fact, for birch pollen allergy a randomized, multicenter double-blind, placebo-controlled clinical trial, including 134 birch pollen allergic patients, was conducted to compare treatment efficacy of recombinant Bet v 1, natural Bet v 1 isolated from birch pollen and a conventional birch pollen. Patients received treatment for 12 weeks in weekly intervals, followed by monthly treatment for a period of 2 years. All actively treated patients demonstrated significant improvement in their rhinoconjunctivitis scores paralleled with reduced skin reactivity. The scores for rescue medication were also significantly reduced in actively treated groups. In addition, Bet v 1 IT resulted in the induction of specific total IgG, IgG1, IgG2a and IgG4, whereas the levels of IgE, IgA and IgG3 remained unaltered. Of note, in three cases extract IT induced de novo sensitizations towards the birch pollen profilin Bet v 2, and in one patient, Bet v 2-specific IgE levels were increased. Interestingly, despite the use of wild-type allergens or extracts, the number of reported side effects was similar to the placebo group. Based on this study, a tablet for sublingual IT of birch pollen allergy is being developed and a first positive report on the efficacy of a dose finding Phase IIb/III study has been already published.
Clinical Studies With Recombinant Wild-type Allergens
In recent years, several clinical studies using recombinant allergens or their derivatives have been published (summarized in Table 2). In general, the complexity of allergen extracts can hamper the development of allergy vaccines based on recombinant proteins. Nevertheless, as discussed in the previous chapters, a multitude of novel concepts engaging this problem have been developed and some have already been tested in clinical trials. The use of recombinant wild-type allergens in IT of grass and birch pollen allergy has proven to be clinically effective. A randomized, double-blind, placebo-controlled trial with 62 subjects performed by Jutel et al. used a combination of five different recombinant grass pollen allergens, including Phl p 1 and Phl p 2, two isoforms of Phl p 5, and Phl p 6 in approximately equimolar concentration. Active treatment, which was performed over a period of 1.5 years, led to the induction of grass pollen-specific IgG1 and IgG4 antibodies, in parallel with a suppression of specific IgE. Moreover, symptom and combined symptom medication scores were significantly improved, and the authors found significant improvement in five of seven separate categories in a rhinitis quality-of-life questionnaire. Adverse events reported in the actively treated group referred, in most cases, to local reactions at the injection site; however, severe systemic reactions, including urticaria, dyspnea and asthma exacerbation, were also reported. Later, a double-blind, placebo-controlled, dose-ranging safety trial using the same cocktail of recombinant grass pollen allergens was conducted. A total of 50 patients were divided into five groups (four active, one placebo) and actively treated groups received either 20, 40, 80 or 120 µg antigen as maximal dose following updosing, which started at 0.156 µg. In total, 13 injections were administered. Adverse systemic side effects grade I and II were reported in eight actively treated subjects, however, the reactions were evenly distributed within the groups. Conjunctival provocation tests were performed to assess treatment efficacy. Interestingly, the group treated with maximal 40 µg antigen showed the best improvement rates in this assay. Active treatment induced IgG1 and IgG4 antibodies against grass pollen, but there was quite some variation between the groups, which made it difficult to interpret the results. Moreover, active treatment had beneficial effects on late-phase reactions as determined by intracutaneous testing. A criticism of the study could be the small sample size. Nevertheless, even high final doses of recombinant allergens did not result in severe side effects, thus encouraging larger follow-up trials. For some allergen sources, such as birch pollen or cat hair, the use of a single disease-dominating allergen might be sufficient for IT. In fact, for birch pollen allergy a randomized, multicenter double-blind, placebo-controlled clinical trial, including 134 birch pollen allergic patients, was conducted to compare treatment efficacy of recombinant Bet v 1, natural Bet v 1 isolated from birch pollen and a conventional birch pollen. Patients received treatment for 12 weeks in weekly intervals, followed by monthly treatment for a period of 2 years. All actively treated patients demonstrated significant improvement in their rhinoconjunctivitis scores paralleled with reduced skin reactivity. The scores for rescue medication were also significantly reduced in actively treated groups. In addition, Bet v 1 IT resulted in the induction of specific total IgG, IgG1, IgG2a and IgG4, whereas the levels of IgE, IgA and IgG3 remained unaltered. Of note, in three cases extract IT induced de novo sensitizations towards the birch pollen profilin Bet v 2, and in one patient, Bet v 2-specific IgE levels were increased. Interestingly, despite the use of wild-type allergens or extracts, the number of reported side effects was similar to the placebo group. Based on this study, a tablet for sublingual IT of birch pollen allergy is being developed and a first positive report on the efficacy of a dose finding Phase IIb/III study has been already published.
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