杭州浙大迪迅生物基因工程有限公司Release date：2019-04-30
JACI
DOI: https://doi.org/10.1016/j.jaci.2017.03.048|
Abstract:
Allergen-specific immunotherapy (AIT) is a clinically and cost-effective allergy treatment that modifies the course of the disease and has long-lasting effects.1x1Cox, L., Calderón, M., and Pfaar, O. Subcutaneous allergen immunotherapy for allergic disease: examining efficacy, safety and cost-effectiveness of current and novel formulations. Immunotherapy. 2012; 4: 601–616
Crossref | PubMed | Scopus (31) | Google ScholarSee all References, E7xE7Jutel, M., Agache, I., Bonini, S., Burks, A.W., Calderon, M., Canonica, W. et al. International consensus on allergy immunotherapy. J Allergy Clin Immunol. 2015; 136: 556–568
Abstract | Full Text | Full Text PDF | PubMed | Scopus (201) | Google ScholarSee all References, E8xE8Jacobsen, L., Niggemann, B., Dreborg, S., Ferdousi, H.A., Halken, S., Host, A. et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy. 2007; 62: 943–948
Crossref | PubMed | Scopus (617) | Google ScholarSee all References However, allergen extract–based forms of AIT require administration of multiple doses, which makes treatment cumbersome and leads to poor compliance in patients.2x2Keil, M.A., Röder, E., Gerth van Wijk, R., Al, M.J., Hop, W.C., and Rutten-van Mölken, M.P. Real-life compliance and persistence among users of subcutaneous and sublingual allergen immunotherapy. J Allergy Clin Immunol. 2013; 132: 353–360
Abstract | Full Text | Full Text PDF | PubMed | Scopus (115) | Google ScholarSee all References A number of approaches were proposed to address this issue, including use of AIT materials with higher safety, such as allergoids, recombinant allergen derivatives, and allergen-derived peptides, which allow shortening of the build-up phase.E9 In this study we have investigated the ability of the recombinant B cell epitope–based allergy vaccine BM32 to induce allergen-specific IgG antibodies and the ability of these antibodies to inhibit allergic patients' IgE binding to grass pollen allergens, as well as allergen-induced T-cell proliferation. BM32 is a recombinant grass pollen (Phleum pratense) allergy vaccine based on 4 fusion proteins consisting of peptides from the 4 major timothy grass pollen allergens (Phl p 1, Phl p 2, Phl p 5, and Phl p 6) fused to the PreS carrier protein from hepatitis B, which lacks relevant allergenic activityE10xE10Niederberger, V., Marth, K., Eckl-Dorna, J., Focke-Tejkl, M., Weber, M., Hemmer, W. et al. Skin test evaluation of a novel peptide carrier-based vaccine, BM32, in grass pollen-allergic patients. J Allergy Clin Immunol. 2015; 136: 1101–1103
Abstract | Full Text | Full Text PDF | PubMed | Scopus (26) | Google ScholarSee all References and therefore can be injected into allergic patients without need for updosing.3x3Focke-Tejkl, M., Weber, M., Niespodziana, K., Neubauer, A., Huber, H., Henning, R. et al. Development and characterization of a recombinant, hypoallergenic, peptide-based vaccine for grass pollen allergy. J Allergy Clin Immunol. 2015; 135: 1207–1217 (e1-11)
Abstract | Full Text | Full Text PDF | PubMed | Google ScholarSee all References, 4x4Zieglmayer, P., Focke-Tejkl, M., Schmutz, R., Lemell, P., Zieglmayer, R., Weber, M. et al. Mechanisms, safety and efficacy of a B cell epitope-based vaccine for immunotherapy of grass pollen allergy. EBioMedicine. 2016; 11: 43–57
Abstract | Full Text | Full Text PDF | PubMed | Scopus (43) | Google ScholarSee all References For our immunogenicity studies, we have used a dose (ie, 20 μg of each of the 4BM fusion proteins) that has been safely administered to allergic patients (ClinicalTrials.gov identifiers NCT01445002, NCT01538979, and NCT02643641).4 x4Zieglmayer, P., Focke-Tejkl, M., Schmutz, R., Lemell, P., Zieglmayer, R., Weber, M. et al. Mechanisms, safety and efficacy of a B cell epitope-based vaccine for immunotherapy of grass pollen allergy. EBioMedicine. 2016; 11: 43–57
Abstract | Full Text | Full Text PDF | PubMed | Scopus (43) | Google ScholarSee all ReferencesThe main finding of our current study was that 3 monthly subcutaneous injections of aluminum hydroxide–adsorbed BM32 induced IgG antibody levels to the major grass pollen allergens Phl p 1, Phl p 5, and Phl p 6 in rabbits, which were comparable with natural allergen extract–based registered grass pollen allergy vaccines requiring more than 8 injections (Allergovit grass; Allergopharma, Reinbek, Germany; Alutard SQ grass mix; ALK-Abelló, Hørsholm, Denmark; and Phostal grasses + rye; Stallergenes, Antony, France; see the MethodsMethods section in this article's Online Repository at www.jacionline.org; Fig 1Fig 1), whereas almost no response was observed with Pollinex (Pollinex Quattro Plus grasses + rye; Bencard Allergie GmbH, Munich, Germany), a vaccine based on 4 injections. Importantly, BM32 induced higher levels of Phl p 2–specific IgG antibodies than any of the registered allergen extract–based vaccines (Fig 1Fig 1). We consider this an important finding because it has been shown that group 2 allergens are major grass pollen allergens recognized by more than 60% of patients with grass pollen allergy and, when compared with the other grass pollen allergens by using skin testing, were found to show high allergenic potency.5x5Westritschnig, K., Horak, F., Swoboda, I., Balic, N., Spitzauer, S., Kundi, M. et al. Different allergenic activity of grass pollen allergens revealed by skin testing. Eur J Clin Invest. 2008; 38: 260–267
Crossref | PubMed | Scopus (42) | Google ScholarSee all References Thus our results indicate that it should be possible to build up sufficient levels of grass pollen allergen–specific IgG responses with only few injections (ie, 3-5) of BM32, whereas traditional allergy vaccines require more than double the number of updosing injections. Sublingual treatment even requires daily administration. Therefore we think that the treatment schedules based on BM32 will be more convenient for patients and should increase their compliance. In the IgE inhibition experiments BM32-induced IgG blocked IgE binding to Phl p 2 significantly better than IgG antibodies induced by the commercial vaccines (P = .0008, Fig 2Fig 2). Therefore one might assume that BM32 could be superior to the extract-based vaccines regarding protection of group 2 allergen–induced symptoms. Finally, we also could demonstrate that BM32-induced antibodies inhibited specifically grass pollen allergen–induced T-cell proliferation (see the MethodsMethods section and Fig E3Fig E3 in this article's Online Repository at www.jacionline.org), which suggests that BM32 might also have beneficial effects on T cell–mediated late-phase symptoms of grass pollen allergy. However, a limitation of our study is that we performed the immunogenicity study in naive animals, and therefore there might be differences regarding already sensitized patients.
In summary, our immunogenicity studies indicate that induction of grass pollen allergen–specific protective antibody responses requires considerably fewer injections of BM32 compared with natural allergen extract–based vaccines and that the use of carrier proteins in the vaccine helps to overcome the poor immunogenicity of group 2 allergens. Given the strong reduction of allergenic activity of BM32, one might expect that BM32 represents a grass pollen allergy vaccine that could be superior to allergen extract–based vaccines.
Authors:
Milena Weber Katarzyna Niespodziana Birgit Linhart Angela Neubauer ,
Hans Huber Rainer Henning Rudolf Valenta
[IF:13.1]
Comparison of the immunogenicity of BM32, a recombinant hypoallergenic B cell epitope–based grass pollen allergy vaccine with allergen extract–based vaccinesDOI: https://doi.org/10.1016/j.jaci.2017.03.048|
Abstract:
Allergen-specific immunotherapy (AIT) is a clinically and cost-effective allergy treatment that modifies the course of the disease and has long-lasting effects.1x1Cox, L., Calderón, M., and Pfaar, O. Subcutaneous allergen immunotherapy for allergic disease: examining efficacy, safety and cost-effectiveness of current and novel formulations. Immunotherapy. 2012; 4: 601–616
Crossref | PubMed | Scopus (31) | Google ScholarSee all References, E7xE7Jutel, M., Agache, I., Bonini, S., Burks, A.W., Calderon, M., Canonica, W. et al. International consensus on allergy immunotherapy. J Allergy Clin Immunol. 2015; 136: 556–568
Abstract | Full Text | Full Text PDF | PubMed | Scopus (201) | Google ScholarSee all References, E8xE8Jacobsen, L., Niggemann, B., Dreborg, S., Ferdousi, H.A., Halken, S., Host, A. et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy. 2007; 62: 943–948
Crossref | PubMed | Scopus (617) | Google ScholarSee all References However, allergen extract–based forms of AIT require administration of multiple doses, which makes treatment cumbersome and leads to poor compliance in patients.2x2Keil, M.A., Röder, E., Gerth van Wijk, R., Al, M.J., Hop, W.C., and Rutten-van Mölken, M.P. Real-life compliance and persistence among users of subcutaneous and sublingual allergen immunotherapy. J Allergy Clin Immunol. 2013; 132: 353–360
Abstract | Full Text | Full Text PDF | PubMed | Scopus (115) | Google ScholarSee all References A number of approaches were proposed to address this issue, including use of AIT materials with higher safety, such as allergoids, recombinant allergen derivatives, and allergen-derived peptides, which allow shortening of the build-up phase.E9 In this study we have investigated the ability of the recombinant B cell epitope–based allergy vaccine BM32 to induce allergen-specific IgG antibodies and the ability of these antibodies to inhibit allergic patients' IgE binding to grass pollen allergens, as well as allergen-induced T-cell proliferation. BM32 is a recombinant grass pollen (Phleum pratense) allergy vaccine based on 4 fusion proteins consisting of peptides from the 4 major timothy grass pollen allergens (Phl p 1, Phl p 2, Phl p 5, and Phl p 6) fused to the PreS carrier protein from hepatitis B, which lacks relevant allergenic activityE10xE10Niederberger, V., Marth, K., Eckl-Dorna, J., Focke-Tejkl, M., Weber, M., Hemmer, W. et al. Skin test evaluation of a novel peptide carrier-based vaccine, BM32, in grass pollen-allergic patients. J Allergy Clin Immunol. 2015; 136: 1101–1103
Abstract | Full Text | Full Text PDF | PubMed | Scopus (26) | Google ScholarSee all References and therefore can be injected into allergic patients without need for updosing.3x3Focke-Tejkl, M., Weber, M., Niespodziana, K., Neubauer, A., Huber, H., Henning, R. et al. Development and characterization of a recombinant, hypoallergenic, peptide-based vaccine for grass pollen allergy. J Allergy Clin Immunol. 2015; 135: 1207–1217 (e1-11)
Abstract | Full Text | Full Text PDF | PubMed | Google ScholarSee all References, 4x4Zieglmayer, P., Focke-Tejkl, M., Schmutz, R., Lemell, P., Zieglmayer, R., Weber, M. et al. Mechanisms, safety and efficacy of a B cell epitope-based vaccine for immunotherapy of grass pollen allergy. EBioMedicine. 2016; 11: 43–57
Abstract | Full Text | Full Text PDF | PubMed | Scopus (43) | Google ScholarSee all References For our immunogenicity studies, we have used a dose (ie, 20 μg of each of the 4BM fusion proteins) that has been safely administered to allergic patients (ClinicalTrials.gov identifiers NCT01445002, NCT01538979, and NCT02643641).4 x4Zieglmayer, P., Focke-Tejkl, M., Schmutz, R., Lemell, P., Zieglmayer, R., Weber, M. et al. Mechanisms, safety and efficacy of a B cell epitope-based vaccine for immunotherapy of grass pollen allergy. EBioMedicine. 2016; 11: 43–57
Abstract | Full Text | Full Text PDF | PubMed | Scopus (43) | Google ScholarSee all ReferencesThe main finding of our current study was that 3 monthly subcutaneous injections of aluminum hydroxide–adsorbed BM32 induced IgG antibody levels to the major grass pollen allergens Phl p 1, Phl p 5, and Phl p 6 in rabbits, which were comparable with natural allergen extract–based registered grass pollen allergy vaccines requiring more than 8 injections (Allergovit grass; Allergopharma, Reinbek, Germany; Alutard SQ grass mix; ALK-Abelló, Hørsholm, Denmark; and Phostal grasses + rye; Stallergenes, Antony, France; see the MethodsMethods section in this article's Online Repository at www.jacionline.org; Fig 1Fig 1), whereas almost no response was observed with Pollinex (Pollinex Quattro Plus grasses + rye; Bencard Allergie GmbH, Munich, Germany), a vaccine based on 4 injections. Importantly, BM32 induced higher levels of Phl p 2–specific IgG antibodies than any of the registered allergen extract–based vaccines (Fig 1Fig 1). We consider this an important finding because it has been shown that group 2 allergens are major grass pollen allergens recognized by more than 60% of patients with grass pollen allergy and, when compared with the other grass pollen allergens by using skin testing, were found to show high allergenic potency.5x5Westritschnig, K., Horak, F., Swoboda, I., Balic, N., Spitzauer, S., Kundi, M. et al. Different allergenic activity of grass pollen allergens revealed by skin testing. Eur J Clin Invest. 2008; 38: 260–267
Crossref | PubMed | Scopus (42) | Google ScholarSee all References Thus our results indicate that it should be possible to build up sufficient levels of grass pollen allergen–specific IgG responses with only few injections (ie, 3-5) of BM32, whereas traditional allergy vaccines require more than double the number of updosing injections. Sublingual treatment even requires daily administration. Therefore we think that the treatment schedules based on BM32 will be more convenient for patients and should increase their compliance. In the IgE inhibition experiments BM32-induced IgG blocked IgE binding to Phl p 2 significantly better than IgG antibodies induced by the commercial vaccines (P = .0008, Fig 2Fig 2). Therefore one might assume that BM32 could be superior to the extract-based vaccines regarding protection of group 2 allergen–induced symptoms. Finally, we also could demonstrate that BM32-induced antibodies inhibited specifically grass pollen allergen–induced T-cell proliferation (see the MethodsMethods section and Fig E3Fig E3 in this article's Online Repository at www.jacionline.org), which suggests that BM32 might also have beneficial effects on T cell–mediated late-phase symptoms of grass pollen allergy. However, a limitation of our study is that we performed the immunogenicity study in naive animals, and therefore there might be differences regarding already sensitized patients.
In summary, our immunogenicity studies indicate that induction of grass pollen allergen–specific protective antibody responses requires considerably fewer injections of BM32 compared with natural allergen extract–based vaccines and that the use of carrier proteins in the vaccine helps to overcome the poor immunogenicity of group 2 allergens. Given the strong reduction of allergenic activity of BM32, one might expect that BM32 represents a grass pollen allergy vaccine that could be superior to allergen extract–based vaccines.
Authors:
Milena Weber Katarzyna Niespodziana Birgit Linhart Angela Neubauer ,
Hans Huber Rainer Henning Rudolf Valenta
2019-4-16 Article
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