Development and evaluation of a sublingual tablet based on recombinant Bet v 1 in birch pollen-allergic patients
R. Vincentelli
Structural Immunology, AFMB-UMR7257, Marseille, France
Search for more papers by this authorP. Leone
Structural Immunology, AFMB-UMR7257, Marseille, France
Search for more papers by this authorA. Roussel
Structural Immunology, AFMB-UMR7257, Marseille, France
Search for more papers by this authorM. Arvidsson
Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, Goteborg, Sweden
Search for more papers by this authorS. Rak
Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, Goteborg, Sweden
Search for more papers by this authorCorresponding Author
P. Moingeon
Stallergenes, Antony, France
Correspondence
Dr. Philippe Moingeon, Research and Development, Stallergenes, 6 rue Alexis de Tocqueville, 92183 Antony Cedex, France.
Tel.: 0033 1 55 59 25 35
Fax: 0033 1 55 59 21 02
E-mail: [email protected]
Search for more papers by this authorR. Vincentelli
Structural Immunology, AFMB-UMR7257, Marseille, France
Search for more papers by this authorP. Leone
Structural Immunology, AFMB-UMR7257, Marseille, France
Search for more papers by this authorA. Roussel
Structural Immunology, AFMB-UMR7257, Marseille, France
Search for more papers by this authorM. Arvidsson
Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, Goteborg, Sweden
Search for more papers by this authorS. Rak
Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, Goteborg, Sweden
Search for more papers by this authorCorresponding Author
P. Moingeon
Stallergenes, Antony, France
Correspondence
Dr. Philippe Moingeon, Research and Development, Stallergenes, 6 rue Alexis de Tocqueville, 92183 Antony Cedex, France.
Tel.: 0033 1 55 59 25 35
Fax: 0033 1 55 59 21 02
E-mail: [email protected]
Search for more papers by this authorAbstract
Background
Sublingual immunotherapy (SLIT) applied to type I respiratory allergies is commonly performed with natural allergen extracts. Herein, we developed a sublingual tablet made of pharmaceutical-grade recombinant Bet v 1.0101 (rBet v 1) and investigated its clinical safety and efficacy in birch pollen (BP)-allergic patients.
Methods
Following expression in Escherichia coli and purification, rBet v 1 was characterized using chromatography, capillary electrophoresis, circular dichroism, mass spectrometry and crystallography. Safety and efficacy of rBet v 1 formulated as a sublingual tablet were assessed in a multicentre, double-blind, placebo-controlled study conducted in 483 patients with BP-induced rhinoconjunctivitis.
Results
In-depth characterization confirmed the intact product structure and high purity of GMP-grade rBet v 1. The crystal structure resolved at 1.2 Å documented the natural conformation of the molecule. Native or oxidized forms of rBet v 1 did not induce the production of any proinflammatory cytokine by blood dendritic cells or mononuclear cells. Bet v 1 tablets were well tolerated by patients, consistent with the known safety profile of SLIT. The average adjusted symptom scores were significantly decreased relative to placebo in patients receiving once daily for 5 months rBet v 1 tablets, with a mean difference of 17.0–17.7% relative to the group treated with placebo (P < 0.025), without any influence of the dose in the range (12.5–50 μg) tested.
Conclusion
Recombinant Bet v 1 has been produced as a well-characterized pharmaceutical-grade biological drug. Sublingual administration of rBet v 1 tablets is safe and efficacious in patients with BP allergic rhinoconjunctivitis.
Supporting Information
| Filename | Description |
|---|---|
| all12622-sup-0001-SupInfo.docxWord document, 255.6 KB | Data S1. Material and methods. Figure S1. Clinical study participant flow. Figure S2. Structural characterization. Figure S3. Functional characterization of native and oxidized rBet v 1. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Breiteneder H, Hassfeld W, Pettenburger K, Jarolim E, Breitenbach M, Rumpold H et al. Isolation and characterization of messenger RNA from male inflorescences and pollen of the white birch (Betula verrucosa). Int Arch Allergy Immunol 1988; 87: 19–24.
- 2Khinchi MS, Poulsen LK, Carat F, Andre C, Hansen AB, Malling HJ. Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized, placebo-controlled, double-blind, double-dummy study. Allergy 2004; 59: 45–53.
- 3Dahl R, Kapp A, Colombo G, de Monchy JG, Rak S, Emminger W et al. Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006; 118: 434–440.
- 4Frew AJ, Powell RJ, Corrigan CJ, Durham SR. Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006; 117: 319–325.
- 5Didier A, Malling HJ, Worm M, Horak F, Jager S, Montagut A et al. Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol 2007; 120: 1338–1345.
- 6Powell RJ, Frew AJ, Corrigan CJ, Durham SR. Effect of grass pollen immunotherapy with Alutard SQ on quality of life in seasonal allergic rhinoconjunctivitis. Allergy 2007; 62: 1335–1338.
- 7Dahl R, Kapp A, Colombo G, de Monchy JG, Rak S, Emminger W et al. Sublingual grass allergen tablet immunotherapy provides sustained clinical benefit with progressive immunologic changes over 2 years. J Allergy Clin Immunol 2008; 121: 512–518.
- 8Cox LS, Casale TB, Nayak AS, Bernstein DI, Creticos PS, Ambroisine L et al. Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: the importance of allergen-specific serum IgE. J Allergy Clin Immunol 2012; 130: 1327–1334.
- 9Worm M, Rak S, de Blay F, Malling HJ, Melac M, Cadic V et al. Sustained efficacy and safety of a 300IR daily dose of a sublingual solution of birch pollen allergen extract in adults with allergic rhinoconjunctivitis: results of a double-blind, placebo-controlled study. Clin Transl Allergy 2014; 4: 7.
- 10Pauli G, Larsen TH, Rak S, Horak F, Pastorello E, Valenta R et al. Efficacy of recombinant birch pollen vaccine for the treatment of birch-allergic rhinoconjunctivitis. J Allergy Clin Immunol 2008; 122: 951–960.
- 11Cromwell O, Hafner D, Nandy A. Recombinant allergens for specific immunotherapy. J Allergy Clin Immunol 2011; 127: 865–872.
- 12Valenta R, Niespodziana K, Focke-Tejkl M, Marth K, Huber H, Neubauer A et al. Recombinant allergens: what does the future hold? J Allergy Clin Immunol 2011; 127: 860–864.
- 13Niederberger V, Horak F, Vrtala S, Spitzauer S, Krauth MT, Valent P et al. Vaccination with genetically engineered allergens prevents progression of allergic disease. Proc Natl Acad Sci USA 2004; 101(Suppl 2): 14677–14682.
- 14Jutel M, Jaeger L, Suck R, Meyer H, Fiebig H, Cromwell O. Allergen-specific immunotherapy with recombinant grass pollen allergens. J Allergy Clin Immunol 2005; 116: 608–613.
- 15Klimek L, Schendzielorz P, Pinol R, Pfaar O. Specific subcutaneous immunotherapy with recombinant grass pollen allergens: first randomized dose-ranging safety study. Clin Exp Allergy 2012; 42: 936–945.
- 16Meyer W, Narkus A, Salapatek AM, Hafner D. Double-blind, placebo-controlled, dose-ranging study of new recombinant hypoallergenic Bet v 1 in an environmental exposure chamber. Allergy 2013; 68: 724–731.
- 17van Ree R, Chapman MD, Ferreira F, Vieths S, Bryan D, Cromwell O et al. The CREATE project: development of certified reference materials for allergenic products and validation of methods for their quantification. Allergy 2008; 63: 310–326.
- 18Vieths S, Barber D, Chapman M, Costanzo A, Daas A, Fiebig H et al. Establishment of recombinant major allergens Bet v 1 and Phl p 5a as Ph. Eur. reference standards and validation of ELISA methods for their measurement. Results from feasibility studies. Pharmeur Bio Sci Notes 2012; 2012: 118–134.
- 19Koberlein J, Mosges R. Oralair((R)): a causal treatment for grass pollen-induced allergic rhinoconjunctivitis. Immunotherapy 2013; 5: 13–21.
- 20Grouin JM, Vicaut E, Jean-Alphonse S, Demoly P, Wahn U, Didier A et al. The average Adjusted Symptom Score, a new primary efficacy end-point for specific allergen immunotherapy trials. Clin Exp Allergy 2011; 41: 1282–1288.
- 21Hirel PH, Schmitter MJ, Dessen P, Fayat G, Blanquet S. Extent of N-terminal methionine excision from Escherichia coli proteins is governed by the side-chain length of the penultimate amino acid. Proc Natl Acad Sci USA 1989; 86: 8247–8251.
- 22Gajhede M, Osmark P, Poulsen FM, Ipsen H, Larsen JN, Joost van Neerven RJ et al. X-ray and NMR structure of Bet v 1, the origin of birch pollen allergy. Nat Struct Biol 1996; 3: 1040–1045.
- 23Kofler S, Asam C, Eckhard U, Wallner M, Ferreira F, Brandstetter H. Crystallographically mapped ligand binding differs in high and low IgE binding isoforms of birch pollen allergen bet v 1. J Mol Biol 2012; 422: 109–123.
- 24Mogensen JE, Wimmer R, Larsen JN, Spangfort MD, Otzen DE. The major birch allergen, Bet v 1, shows affinity for a broad spectrum of physiological ligands. J Biol Chem 2002; 277: 23684–23692.
- 25Seutter von Loetzen C, Hoffmann T, Hartl MJ, Schweimer K, Schwab W, Rosch P et al. Secret of the major birch pollen allergen Bet v 1: identification of the physiological ligand. Biochem J 2014; 457: 379–390.
- 26Marth K, Focke-Tejkl M, Lupinek C, Valenta R, Niederberger V. Allergen peptides, recombinant allergens and hypoallergens for allergen-specific immunotherapy. Curr Treat Options Allergy 2014; 1: 91–106.
- 27Breiteneder H, Valenta R. Recombinant allergen methods. Methods 2014; 66: 1–2.
- 28Himly M, Nony E, Chabre H, Van Overtvelt L, Neubauer A, van Ree R et al. Standardization of allergen products: 1. Detailed characterization of GMP-produced recombinant Bet v 1.0101 as biological reference preparation. Allergy 2009; 64: 1038–1045.
- 29Barral P, Tejera ML, Trevino MA, Batanero E, Villalba M, Bruix M et al. Recombinant expression of Ole e 6, a Cys-enriched pollen allergen, in Pichia pastoris yeast: detection of partial oxidation of methionine by NMR. Protein Exp Purif 2004; 37: 336–343.
- 30Nopp A, Hallden G, Lundahl J, Johansson E, Vrtala S, Valenta R et al. Comparison of inflammatory responses to genetically engineered hypoallergenic derivatives of the major birch pollen allergen bet v 1 and to recombinant bet v 1 wild type in skin chamber fluids collected from birch pollen-allergic patients. J Allergy Clin Immunol 2000; 106: 101–109.
- 31Roth-Walter F, Gomez-Casado C, Pacios LF, Mothes-Luksch N, Roth GA, Singer J et al. Bet v 1 from birch pollen is a lipocalin-like protein acting as allergen only when devoid of iron by promoting Th2 lymphocytes. J Biol Chem 2014; 289: 17416–17421.
- 32Gidaro GB, Marcucci F, Sensi L, Incorvaia C, Frati F, Ciprandi G. The safety of sublingual-swallow immunotherapy: an analysis of published studies. Clin Exp Allergy 2005; 35: 565–571.
- 33Calderon MA, Simons FE, Malling HJ, Lockey RF, Moingeon P, Demoly P. Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile. Allergy 2012; 67: 302–311.
- 34Moingeon P. Update on immune mechanisms associated with sublingual immunotherapy: practical implications for the clinician. J Allergy Clin Immunol Pract 2013; 1: 228–241.
- 35Tourdot S, Airouche S, Berjont N, Moussu H, Betbeder D, Nony E et al. Efficacy of sublingual vectorized recombinant Bet v 1a in a mouse model of birch pollen allergic asthma. Vaccine 2013; 31: 2628–2637.
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