Allergen exposure chambers: implementation in clinical trials in allergen immunotherapy

Abstract Allergen exposure chambers (AECs) have been developed for controlled allergen challenges of allergic patients mimicking natural exposure. As such, these facilities have been utilized e.g., for proof of concept, dose finding or the demonstration of onset of action and treatment effect sizes of antiallergic medication. Moreover, clinical effects of and immunological mechanisms in allergen immunotherapy (AIT) have been investigated in AECs. In Europe AIT products have to fulfill regulatory requirements for obtaining market authorization through Phase I to III clinical trials. Multiple Phase II (dose-range-finding or proof-of-concept) trials on AIT products have been performed in AECs. However, they are not accepted by regulatory bodies for pivotal (Phase III) trials and a more thorough technical and clinical validation is requested. Recently, a Position Paper of the European Academy of Allergy and Clinical Immunology (EAACI) has outlined unmet needs in further development of AECs. The following review aims to address some of these needs on the basis of recently published data in the first part, whereas the second part overviews published examples of most relevant Phase II trials in AIT performed in AEC facilities

Carrageenan-Containing Nasal Spray Alleviates Allergic Symptoms in Participants with Grass Pollen Allergy: A Randomized, Controlled, Crossover Clinical Trial

Nicole Unger-Manhart,1,* Martina Morokutti-Kurz,1,* Petra U Zieglmayer,2,3 Patrick Lemell,2 Markus Savli,4 René Zieglmayer,2 Eva Prieschl-Grassauer1 1Marinomed Biotech AG, Korneuburg, Austria; 2Vienna Challenge Chamber, Vienna, Austria; 3Competence Center for Allergology and Immunology, Karl Landsteiner University, Krems, Austria; 4Biostatistik & Consulting GmbH, Zurich, Switzerland*These authors contributed equally to this workCorrespondence: Eva Prieschl-Grassauer, Marinomed Biotech AG, Hovengasse 25, Korneuburg, 2100, Austria, Tel +43 226292300, Email [email protected]: Nonpharmacological, barrier-forming nasal sprays are used to manage symptoms of allergic rhinitis. We aim to evaluate the safety and effectiveness of Callergin (investigational product, IP), a nasal spray containing barrier-forming iota-carrageenan, in the treatment of allergic rhinitis (AR).Methods: In this randomized, controlled, crossover trial, adults with grass pollen allergy underwent a treatment sequence with IP, VisAlpin (comparator product, CP), and no treatment in random order. Treatment blocks consisted in prophylactic administration of the assigned treatment or no treatment, followed by a 3-hr allergen exposure, and were separated by a washout period of 7 days. Primary endpoint was a mean change from baseline in “Total Nasal Symptom Score” (TNSS, sum of rhinorrhea, itching, sneezing, and congestion scores) over 3 hr, recorded every 15 min during the challenge period.Results: A total of 42 participants underwent randomization. Exposure to grass pollen for 3 hr induced a notable TNSS increase from baseline in all participants at all times. Mean TNSS change from baseline over 3 hr was lower when participants received IP compared to no treatment, although the difference did not reach statistical significance (untreated 6.96 ± 2.30; IP 6.59 ± 1.93; difference 0.37 points [95% CI (confidence interval) − 0.17 to 0.91]; p=0.170). In a post-hoc analysis, mean TNSS at 3 hr was significantly reduced after IP treatment compared to no treatment (untreated 8.29 ± 2.64; IP 7.70 ± 2.56; difference 0.60 points [95% CI − 0.10 to 1.29] p=0.028). While all individual nasal symptoms contributed to this effect, rhinorrhea (p=0.013) and congestion (p=0.076) contributed most. Consistently, nasal secretion weight was slightly reduced with IP treatment (p=0.119). IP was safe and well-tolerated, with similar incidence of adverse events across treatment groups.Conclusion: Prophylactic treatment with the iota-carrageenan nasal spray IP is safe, well-tolerated, and alleviates nasal allergy symptoms in adults with grass pollen-induced AR.Trial Registration: NCT04531358.Keywords: allergic rhinitis, nonpharmacological, drug-free, barrier, iota-carrageena

Epitope specificity determines cross-protection of a SIT-induced IgG4 antibody

The calcium-binding 2EF-hand protein Phl p 7 from timothy grass pollen is a highly cross-reactive pollen pan-allergen that can induce severe clinical symptoms in allergic patients. Recently, a human monoclonal Phl p 7-specific IgG4 antibody (mAb102.1F10) was isolated from a patient who had received grass pollen-specific immunotherapy (SIT).We studied epitope specificity, cross-reactivity, affinity and cross-protection of mAb102.1F10 towards homologous calcium-binding pollen allergens. Sequence comparisons and molecular modelling studies were performed with ClustalW and SPADE, respectively. Surface plasmon resonance measurements were done with purified recombinant allergens. Binding and cross-reactivity of patients’ IgE and mAb102.1F10 to calcium-binding allergens and peptides thereof was studied with quantitative RAST-based methods, in ELISA, basophil activation and IgE-facilitated allergen presentation experiments. Allergens from Timothy grass (Phl p 7), Alder (Aln g 4), Birch (Bet v 4), Turnip rape (Bra r 1), Lamb′s quarter (Che a 3) and Olive (Ole e 3, Ole e 8) showed high sequence similarity and cross-reacted with allergic patients’ IgE. mAb102.1F10 bound the C-terminal portion of Phl p 7 in a calcium-dependent manner. It cross-reacted with high affinity with Ole e 3 whereas binding and affinity to the other allergens was low. mAb102.1F10 showed limited inhibition of patients’ IgE binding and basophil activation. Sequence comparison and surface exposure calculations identified three amino acids likely to be responsible for limited cross-reactivity.Our results demonstrate that a small number of amino acid differences among cross-reactive allergens can reduce the affinity of binding by a SIT-induced IgG and thus limit cross-protection

Perspectives in allergen immunotherapy: 2017 and beyond

The Future of the Allergists and Specific Immunotherapy (FASIT) workshop provides a regular platform for global experts from academia, allergy clinics, regulatory authorities and industry to review developments in the field of allergen immunotherapy (AIT). The most recent meeting, held in February 2017, had two main themes: advances in AIT and hot topics in AIT from the regulatory point of view. The first theme covered opportunities for personalized AIT, advances in adjuvants and delivery systems, and the development of new molecules and future vaccines for AIT. Key topics in the second part of the meeting were the effects of the enactment of European Directive 2001/83 on the availability of allergens for therapy and diagnosis across the EU, the challenges of conducting Phase 3 studies in the field, the future role of allergen exposure chambers in AIT studies and specific considerations in performing AIT studies in the paediatric population. Finally, the group highlighted the forthcoming EAACI guidelines and their particular importance for the standardization of practice in the treatment of allergies. This review presents a comprehensive insight into those panel discussions and highlights unmet needs and also possible solutions to them for the future