Response to Correspondence ALL-2023-01107 “Short-course subcutaneous treatment with PQ Grass strongly improves symptom and medication scores in grass allergy”P.J. de Kam1, S. Zielen2, J.A. Bernstein3, U. Berger4, M. Berger5, M. Cuevas6, D. Cypcar7, A. Fuhr-Horst8, W.A. Greisner9, M. Jandl10, S. Laßmann11, M. Worm12, J. Matz13, E. Sher14, C. Smith15, G.C. Steven16, R. Mösges17,18, M.H. Shamji19,20, L. DuBuske21, F. Borghese1, K. Oluwayi1, T. Zwingers1, M. Seybold1, O. Armfield1, M.D. Heath1, S.J. Hewings1, M.F. Kramer1, M.A. Skinner1Allergy Therapeutics plc, Worthing, United KingdomChildren and Adolescents Dept., Allergology, Pulmonology & Cystic fibrosis, Goethe University, Frankfurt, GermanyBernstein Clinical Research Center, LLC, Cincinnati, OH, United States of AmericaAerobiology and Pollen Research Unit, Dept. Oto-Rhino-Laryngology, Medical University Vienna, Vienna, Austria.Wiener Gesundheitsverbund, Hospital Hietzing, Department of Otorhinolaryngology, Vienna, AustriaClinic and Polyclinic of Otorhinolaryngology, University Clinic Carl Gustav Carus, TU Dresden, GermanyAllergy Partners of Western North Carolina, Asheville, NC, United States of AmericaENT Research- Institut für klinische Studien, Essen, GermanyBluegrass Allergy Research, Lexington, KY, United States of AmericaHamburger Institut für Therapieforschung GmbH, Hamburg, GermanyStudienzentrum Dr. Sabine Laßmann, Saalfeld, GermanyUniversitätsmedizin Berlin, Department of Dermatology and Allergy - Charite Campus Mitte, Berlin, GermanyChesapeake Clinical Research, Inc. White Marsh, MD, United States of AmericaAllergy Partners of New Jersey, Ocean, NJ, United States of AmericaCertified Research Associates, Cortland, NY, United States of AmericaAllergy Asthma & Sinus Center, S.C., Greenfield, WI, United States of AmericaIMSB (Institute of Computational Biology and Medical Statistics), University at Cologne, Cologne, GermanyClinCompetence, Cologne, GermanyImmunomodulation and Tolerance Group, Allergy and Clinical Immunology, Department of National Heart and Lung Institute, Imperial College London, London, United KingdomAsthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United KingdomDivision of Allergy and Immunology, Department of Internal Medicine, George Washington University Hospital, Washington, DC, United States of America

Type I hypersensitivity, also known as classical allergy, is mediated via allergen-specific IgE antibodies bound to type I FcR (FcεRI) on the surface of mast cells and basophils upon cross-linking by allergens. This IgE-mediated cellular activation may be blocked by allergen-specific IgG through multiple mechanisms, including direct neutralization of the allergen or engagement of the inhibitory receptor FcγRIIb which blocks IgE signal transduction. In addition, co-engagement of FcεRI and FcγRIIb by IgE-IgG-allergen immune-complexes causes down-regulation of receptor bound IgE, resulting in desensitization of the cells. Both, activation of FcεRI by allergen-specific IgE and engagement of FcγRIIb by allergen-specific IgG are driven by allergen-binding. Here we delineate the distinct roles of antibody affinity versus avidity in driving these processes and discuss the role of IgG subclasses in inhibiting basophil and mast cell activation.

CORRIGENDUMDate: 09 Feb 2024Manuscript number: ALL-2023-01229.R1Title of Article: Response to Correspondence ALL-2023-01107 “Short-course subcutaneous treatment with PQ Grass strongly improves symptom and medication scores in grass allergy”Authors: P.J. de Kam1, S. Zielen2, J.A. Bernstein3, U. Berger4, M. Berger5, M. Cuevas6, D. Cypcar7, A. Fuhr-Horst8, W.A. Greisner9, M. Jandl10, S. Laßmann11, M. Worm12, J. Matz13, E. Sher14, C. Smith15, G.C. Steven16, R. Mösges17,18, M.H. Shamji19,20, L. DuBuske21, F. Borghese1, K. Oluwayi1, T. Zwingers1, M. Seybold1, O. Armfield1, M.D. Heath1, S.J. Hewings1, M.F. Kramer1, M.A. Skinner1Allergy Therapeutics plc, Worthing, United KingdomChildren and Adolescents Dept., Allergology, Pulmonology & Cystic fibrosis, Goethe University, Frankfurt, GermanyBernstein Clinical Research Center, LLC, Cincinnati, OH, United States of AmericaUniversity of Innsbruck, Department of Botany, Innsbruck, AustriaWiener Gesundheitsverbund, Hospital Hietzing, Department of Otorhinolaryngology, Vienna, AustriaClinic and Polyclinic of Otorhinolaryngology, University Clinic Carl Gustav Carus, TU Dresden, GermanyAllergy Partners of Western North Carolina, Asheville, NC, United States of AmericaENT Research- Institut für klinische Studien, Essen, GermanyBluegrass Allergy Research, Lexington, KY, United States of AmericaHamburger Institut für Therapieforschung GmbH, Hamburg, GermanyStudienzentrum Dr. Sabine Laßmann, Saalfeld, GermanyUniversitätsmedizin Berlin, Department of Dermatology and Allergy - Charite Campus Mitte, Berlin, GermanyChesapeake Clinical Research, Inc. White Marsh, MD, United States of AmericaAllergy Partners of New Jersey, Ocean, NJ, United States of AmericaCertified Research Associates, Cortland, NY, United States of AmericaAllergy Asthma & Sinus Center, S.C., Greenfield, WI, United States of AmericaIMSB (Institute of Computational Biology and Medical Statistics), University at Cologne, Cologne, GermanyClinCompetence, Cologne, GermanyImmunomodulation and Tolerance Group, Allergy and Clinical Immunology, Department of National Heart and Lung Institute, Imperial College London, London, United KingdomAsthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United KingdomDivision of Allergy and Immunology, Department of Internal Medicine, George Washington University Hospital, Washington, DC, United States of AmericaName of the Corresponding Author: Pieter-Jan De Kam

Background: We previously proposed the whey protein beta-lactoglobulin (BLG) loaded with iron-siderophore complexes as the active principle in the farm protective effect against allergies. A lozenge as food for specific medical purposes (FSMP) was formulated to assess its therapeutical efficacy in BALB/c mice and in-vitro experiments. Methods: Binding of iron-catechin into BLG was confirmed by spectroscopy and docking calculations. Serum IgE binding of children allergic to milk, or tolerating milk, was assessed to loaded (holo-) versus empty (apo-) BLG and for human mast cell degranulation. BLG and Bet v 1 double-sensitized mice were orally treated with the lozenge or placebo, and immunologically analysed after systemic allergen challenge. Human PBMCs of pollen allergic subjects were flow cytometrically assessed after stimulation with holoBLG in conjugation with catechin-iron complexes as ligands in a dietary supplement or with the apoBLG. Results: One major IgE- and T cell epitope were masked by catechin-iron complexes, which impaired IgE binding of milk allergic children and degranulation of mast cells. In mice, only supplementation with the lozenge reduced clinical reactivity to BLG and Bet v 1, promoted Tregs, and suppressed antigen presentation. In allergic subjects, stimulation of PBMCs with holoBLG led to a significant increase of intracellular iron in circulating CD14+ cells with significantly lower expression of HLADR and CD86 compared to their stimulation with apoBLG. Conclusion: The FSMP lozenge targeted antigen presenting cells and dampened immune activation in human immune cells and allergic mice in an antigen nonspecific manner, thereby conferring immune resilience against allergic symptoms.

Type I hypersensitivity, also known as classical allergy, is mediated via allergen-specific IgE antibodies bound to type I FcR (FcεRI) on the surface of mast cells and basophils upon cross-linking by allergens. This IgE-mediated cellular activation may be blocked by allergen-specific IgG through multiple mechanisms, including direct neutralization of the allergen or engagement of the inhibitory receptor FcγRIIb which blocks IgE signal transduction. In addition, co-engagement of FceRI and FcγRIIb by IgE-IgG-allergen immune-complexes causes down-regulation of receptor bound IgE, resulting in desensitization of the cells. Both, activation of FceRI by allergen-specific IgE and engagement of FcγRIIb by allergen-specific IgG are driven by allergen-binding. Here we delineate the distinct roles of antibody affinity versus avidity in driving these processes and discuss the role of IgG subclasses in inhibiting basophil and mast cell activation.