Biologic drugs and allergen immunotherapy: potential allies

Abstract

Allergen-specific immunotherapy (AIT) is a proven efficacy treatment for allergic rhinitis (AR), asthma, and Hymenoptera venom allergy, but its use in food allergy (FA) is still under investigation. Because some efficacy and safety concerns still remain, biologic drugs, including omalizumab and dupilumab, have been studied as an adjunctive therapy to AIT for these conditions. In this article, the evidence supporting the use of monoclonal antibodies (mAbs) as an add-on therapy to AIT for FA, AR, asthma, and Hymenoptera venom allergy has been reviewed. The review will delve into the mechanisms of action of different mAbs, their efficacy, and how they can be integrated into personalized medicine approaches to treat allergic diseases. Furthermore, future research areas will be considered. Evidence suggests that omalizumab in combination with AIT may be a beneficial option for respiratory allergies or food desensitisation, especially during the escalation or build-up phase, when adverse events are more frequent. Currently, there is a small number of well-structured clinical trials in Hymenoptera venom allergy, and the available data consist mainly of single-case reports that provide information of limited value. Dupilumab has been studied as adjunctive therapy in patients with respiratory and FAs. Clinical trials are ongoing to evaluate the efficacy of dupilumab as monotherapy or as an adjunct to oral immunotherapy (OIT) in peanut allergy. Other studies are investigating the use of dupilumab in patients with multiple FAs and as an adjunct to milk OIT. Overall, mAbs have the potential to improve outcomes in various allergic conditions when used as an add-on to AIT, especially during the build-up phase. Further research is needed to fully understand their optimal dosing and duration of treatment, as well as to identify which patients may benefit the most from these therapies.

Keywords

Allergen-specific immunotherapy / biologic agents / monoclonal antibodies / omalizumab / dupilumab / food allergy / respiratory allergy / Hymenoptera venom allergy

References

[1] Palomares O, Akdis M, Martín-Fontecha M, Akdis CA. Mechanisms of immune regulation in allergic diseases: the role of regulatory T and B cells. Immunol Rev. 2017; 278: 219-36.

[2] Głobińska A, Boonpiyathad T, Satitsuksanoa P, Kleuskens M, van de Veen W, Sokolowska M, et al. Mechanisms of allergen-specific immunotherapy. Ann Allergy Asthma Immunol. 2018; 121: 306-12.

[3] Lao-Araya M, Steveling E, Scadding GW, Durham SR, Shamji MH. Seasonal increases in peripheral innate lymphoid type 2 cells are inhibited by subcutaneous grass pollen immunotherapy. J Allergy Clin Immunol. 2014; 134: 1193-5.E4.

[4] Adis Comments . Omalizumab: anti-IgE monoclonal antibody E25, E25, humanised anti-IgE MAb, IGE 025, monoclonal antibody E25, olizumab, Xolair, rhuMAb-E25. BioDrugs. 2002; 16: 380-6.

[5] Arm JP, Bottoli I, Skerjanec A, Floch D, Groenewegen A, Maahs S, et al. Pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody, in atopic subjects. Clin Exp Allergy. 2014; 44: 1371-85.

[6] Hans BD, Lin LY, Lin Z, Tan M, Meng GY, Mercedesz B, et al. Quilizumab is an afucosylated humanized anti-M1 prime therapeutic antibody. Clin Anti Inflamm Anti Allergy Drugs. 2014; 1: 24-31.

[7] MacGlashan D. Loss of receptors and IgE in vivo during treatment with anti-IgE antibody . J Allergy Clin Immunol. 2004; 114: 1472-4.

[8] Kuehr J, Brauburger J, Zielen S, Schauer U, Kamin W, Von Berg A, et al. Efficacy of combination treatment with anti-IgE plus specific immunotherapy in polysensitized children and adolescents with seasonal allergic rhinitis. J Allergy Clin Immunol. 2002; 109: 274-80.

[9] Casale TB, Busse WW, Kline JN, Ballas ZK, Moss MH, Townley RG, et al. ; Immune Tolerance Network Group. Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis. J Allergy Clin Immunol. 2006; 117: 134-40.

[10] Kopp MV, Hamelmann E, Zielen S, Kamin W, Bergmann KC, Sieder C, et al. ; DUAL study group. Combination of omalizumab and specific immunotherapy is superior to immunotherapy in patients with seasonal allergic rhinoconjunctivitis and co-morbid seasonal allergic asthma. Clin Exp Allergy. 2009; 39: 271-9.

[11] Massanari M, Nelson H, Casale T, Busse W, Kianifard F, Geba GP, et al. Effect of pretreatment with omalizumab on the tolerability of specific immunotherapy in allergic asthma. J Allergy Clin Immunol. 2010; 125: 383-9.

[12] Stelmach I, Majak P, Jerzyńska J, Bojo M, Cichalewski Ł, Smejda K. Children with severe asthma can start allergen immunotherapy after controlling asthma with omalizumab: a case series from Poland. Arch Med Sci. 2015; 11: 901-4.

[13] Valdesoiro-Navarrete L, León ME, Rodríguez M, Indiveri M, Ayats R, Larramona H, et al. Combination therapy of specific aeroallergens immunotherapy and omalizumab, in children with severe asthma. Allergol Immunopathol (Madr). 2022; 50: 1-6.

[14] Kopp MV, Hamelmann E, Bendiks M, Zielen S, Kamin W, Bergmann KC, et al. ; DUAL study group. Transient impact of omalizumab in pollen allergic patients undergoing specific immunotherapy. Pediatr Allergy Immunol. 2013; 24: 427-33.

[15] Bożek A, Fischer A, Bogacz-Piaseczynska A, Canonica GW. Adding a biologic to allergen immunotherapy increases treatment efficacy. ERJ Open Res. 2023; 9: 00639-2022.

[16] Pfützner W, Schuppe M. Use of biologics in allergen immunotherapy. Allergol Select. 2021; 5: 108-18.

[17] De Filippo M, Votto M, Caminiti L, Carella F, Castro G, Landi M, et al. Omalizumab and allergen immunotherapy for respiratory allergies: a mini-review from the Allergen-Immunotherapy Committee of the Italian Society of Pediatric Allergy and Immunology (SIAIP). Allergol Immunopathol (Madr). 2022; 50: 47-52.

[18] Boyle RJ, Elremeli M, Hockenhull J, Cherry MG, Bulsara MK, Daniels M, et al. Venom immunotherapy for preventing allergic reactions to insect stings. Cochrane Database Syst Rev. 2012; 10: CD008838.

[19] Sturm GJ, Varga EM, Roberts G, Mosbech H, Bilò MB, Akdis CA, et al. EAACI guidelines on allergen immunotherapy: Hymenoptera venom allergy. Allergy. 2018; 73: 744-64.

[20] Soriano Gomis V, Gonzalez Delgado P, Niveiro Hernandez E . Failure of omalizumab treatment after recurrent systemic reactions to bee-venom immunotherapy. J Investig Allergol Clin Immunol. 2008; 18: 225-6.

[21] Wedi B, Wieczorek D, Roap V, Kapp A. Anti IgE treatment overcomes intolerability of honeybee-venom ultrarush immunotherapy in indolent systemic mastocytosis. J World Allergy Org. 2007; Suppl 2: 182-3.

[22] Schulze J, Rose M, Zielen S. Beekeepers anaphylaxis: successful immunotherapy covered by omalizumab. Allergy. 2007; 62: 963-4.

[23] Averbeck M, Gebhardt C, Renner R, Simon J, Treudler R. Omalizumab helps to induce tolerability in a patient with wasp venom allergy and repeated adverse reactions during specific immunotherapy. Allergy. 2008: 1406.

[24] Rerinck HC, Rueff F, Przybilla B. Recurrent severe anaphylactic reactions to venom immunotherapy (VIT): omalizumab induces tolerance. J Allergy Clin Immunol. 2008; 121: S29.

[25] Galera C, Soohun N, Zankar N, Caimmi S, Gallen C, Demoly P. Severe anaphylaxis to bee venom immunotherapy: efficacy of pretreatment and concurrent treatment with omalizumab. J Investig Allergol Clin Immunol. 2009; 19: 225-9.

[26] Kontou-Fili K, Filis CI . Prolonged high-dose omalizumab is required to control reactions to venom immunotherapy in mastocytosis. Allergy. 2009; 64: 1384-5.

[27] González-Pérez R, Poza-Guedes P, Sánchez-Machín I, Matheu V, Martínez-Tadeo J, Rodríguez E, editors. Successful adyuvant use of omalizumab in life-threatening bee-venom anaphylaxis (EAACI 2010). Proceedings of EAACI 2010; 2010 Jun 5-9; London, UK. EAACI; 2010.

[28] Palgan K, Bartuzi Z, Gotz-Zbikowska M. Treatment with a combination of omalizumab and specific immunotherapy for severe anaphylaxis after a wasp sting. Int J Immunopathol Pharmacol. 2014; 27: 109-12.

[29] da Silva EN, Randall KL. Omalizumab mitigates anaphylaxis during ultrarush honey bee venom immunotherapy in monoclonal mast cell activation syndrome. J Allergy Clin Immunol Pract. 2013; 1: 687-8.

[30] Boni E, Incorvaia C, Mauro M. Dose-dependence of protection from systemic reactions to venom immunotherapy by omalizumab. Clin Mol Allergy. 2016; 14: 14.

[31] Stretz E, Oppel EM, Räwer HC, Chatelain R, Mastnik S, Przybilla B, et al. Overcoming severe adverse reactions to venom immunotherapy using anti-IgE antibodies in combination with a high maintenance dose. Clin Exp Allergy. 2017; 47: 1631-9.

[32] Toldrá S, Farzanegan R, Aleixos M, editors. Bee venom immunotherapy only tolerated with concurrent treatment with omalizumab. Proceedings of EAACI 2017; 2017 Jun 17-21; Helsinki, Finland. EAACI; 2017.

[33] Lourenço T, Lopes A, Caiado J, editors. Omalizumab in immunotherapy with Hymenoptera venom. Proceedings of EAACI 2017; 2017 Jun 17-21; Helsinki, Finland. EAACI; 2017.

[34] Lopes JB, Barreira P, Moreira Da Silva JP, editors. Omalizumab in prevention of anaphylaxis due to bee venom immunotherapy. Proceedings of EAACI 2017; 2017 Jun 17-21; Helsinki, Finland. EAACI; 2017.

[35] Yılmaz İ, Bahçecioğlu SN, Türk M. Combination of omalizumab and bee venom immunotherapy: does it work? Asia Pac Allergy. 2018; 8: e2.

[36] Droitcourt C, Ponvert C, Dupuy A, Scheinmann P, Abou-Taam R, de Blic J, et al. Efficacy of a short pretreatment with omalizumab in children with anaphylaxis to Hymenoptera venom immunotherapy: a report of three cases. Allergol Int. 2019; 68: 268-9.

[37] Gülsen A, Ruëff F, Jappe U. Omalizumab ensures compatibility to bee venom immunotherapy (VIT) after VIT-induced anaphylaxis in a patient with systemic mastocytosis. Allergol Select. 2021; 5: 128-32.

[38] Çetin GP, Yılmaz İ, Türk M, Arslan B, Bahçecioğlu SN. Venom immunotherapy and difficulties encountered before and during immunotherapy: double sensitization, systemic reactions, treatment with omalizumab, and high dose VIT. Turk J Med Sci. 2022; 52: 1223-4.

[39] Ridolo E, Pellicelli I, Kihlgren P, Nizi MC, Pucciarini F, Senna G, et al. Immunotherapy and biologicals for the treatment of allergy to Hymenoptera stings. Expert Opin Biol Ther. 2019; 19: 919-25.

[40] FDA approves first drug for treatment of peanut allergy for children [Internet]. FDA; [cited 2023 Sep 25]. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treatment-peanut-allergy-children

[41] Gernez Y, Nowak-Węgrzyn A. Immunotherapy for food allergy: are we there yet? J Allergy Clin Immunol Pract. 2017; 5: 250-72. Erratum in: J Allergy Clin Immunol Pract. 2017; 5:1167.

[42] Chu DK, Wood RA, French S, Fiocchi A, Jordana M, Waserman S, et al. Oral immunotherapy for peanut allergy (PACE): a systematic review and meta-analysis of efficacy and safety. Lancet. 2019; 393: 2222-32. Erratum in: Lancet. 2019; 393:1936.

[43] Nadeau KC, Schneider LC, Hoyte L, Borras I, Umetsu DT. Rapid oral desensitization in combination with omalizumab therapy in patients with cow’s milk allergy. J Allergy Clin Immunol. 2011; 127: 1622-4.

[44] Bégin P, Winterroth LC, Dominguez T, Wilson SP, Bacal L, Mehrotra A, et al. Safety and feasibility of oral immunotherapy to multiple allergens for food allergy. Allergy Asthma Clin Immunol. 2014; 10: 1. Erratum in: Allergy Asthma Clin Immunol. 2016;12:28.

[45] Martorell-Calatayud C, Michavila-Gómez A, Martorell-Aragonés A, Molini-Menchón N, Cerdá-Mir JC, Félix-Toledo R, et al. Anti-IgE-assisted desensitization to egg and cow’s milk in patients refractory to conventional oral immunotherapy. Pediatr Allergy Immunol. 2016; 27: 544-6.

[46] Wood RA, Kim JS, Lindblad R, Nadeau K, Henning AK, Dawson P, et al. A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow’s milk allergy. J Allergy Clin Immunol. 2016; 137: 1103-10.E11.

[47] MacGinnitie AJ, Rachid R, Gragg H, Little SV, Lakin P, Cianferoni A, et al. Omalizumab facilitates rapid oral desensitization for peanut allergy. J Allergy Clin Immunol. 2017; 139: 873-81.E8.

[48] Takahashi M, Soejima K, Taniuchi S, Hatano Y, Yamanouchi S, Ishikawa H, et al. Oral immunotherapy combined with omalizumab for high-risk cow’s milk allergy: a randomized controlled trial. Sci Rep. 2017; 7: 17453. Erratum in: Sci Rep. 2018;8:12812.

[49] Andorf S, Purington N, Block WM, Long AJ, Tupa D, Brittain E, et al. Anti-IgE treatment with oral immunotherapy in multifood allergic participants: a double-blind, randomised, controlled trial. Lancet Gastroenterol Hepatol. 2018; 3: 85-94.

[50] Andorf S, Purington N, Kumar D, Long A, O’Laughlin KL, Sicherer S, et al. A phase 2 randomized controlled multisite study using omalizumab-facilitated rapid desensitization to test continued vs discontinued dosing in multifood allergic individuals . EClinicalMedicine. 2019; 7: 27-38.

[51] Sindher SB, Kumar D, Cao S, Purington N, Long A, Sampath V, et al. Phase 2, randomized multi oral immunotherapy with omalizumab ‘real life’ study. Allergy. 2022; 77: 1873-84.

[52] Omalizumab as monotherapy and as adjunct therapy to multi-allergen OIT in food allergic participants (OUtMATCH) [Internet]. ClinicalTrials.gov; [cited 2023 Sep 25]. Available from: https://clinicaltrials.gov/ct2/show/NCT03881696

[53] Efficacy and safety of QGE031 (ligelizumab) in patients with peanut allergy [Internet]. ClinicalTrials.gov; [cited 2023 Sep 25]. Available from: https://clinicaltrials.gov/ct2/show/NCT04984876

[54] Peanut reactivity reduced by oral tolerance in an anti-IgE clinical trial (PRROTECT) [Internet]. ClinicalTrials.gov; [cited 2023 Sep 25]. Available from: https://clinicaltrials.gov/ct2/show/NCT01781637

[55] Zuberbier T, Wood RA, Bindslev-Jensen C, Fiocchi A, Chinthrajah RS, Worm M, et al. Omalizumab in IgE-mediated food allergy: a systematic review and meta-analysis. J Allergy Clin Immunol Pract. 2023; 11: 1134-46.

[56] Gomez G. Current strategies to inhibit high affinity FcεRI-mediated signaling for the treatment of allergic disease. Front Immunol. 2019; 10: 175.

[57] Gasser P, Tarchevskaya SS, Guntern P, Brigger D, Ruppli R, Zbären N, et al. The mechanistic and functional profile of the therapeutic anti-IgE antibody ligelizumab differs from omalizumab. Nat Commun. 2020; 11: 165.

[58] Balbino B, Conde E, Marichal T, Starkl P, Reber LL. Approaches to target IgE antibodies in allergic diseases. Pharmacol Ther. 2018; 191: 50-64.

[59] DUPIXENT^® (dupilumab) injection, for subcutaneous use Initial U.S. Approval: 2017 [Internet]. FDA; [cited 2023 Sep 25]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761055s044lbl.pdf

[60] Corren J, Saini SS, Gagnon R, Moss MH, Sussman G, Jacobs J, et al. Short-term subcutaneous allergy immunotherapy and dupilumab are well tolerated in allergic rhinitis: a randomized trial. J Asthma Allergy. 2021; 14: 1045-63.

[61] Rial MJ, Barroso B, Sastre J. Dupilumab for treatment of food allergy. J Allergy Clin Immunol Pract. 2019; 7: 673-4.

[62] Study to evaluate dupilumab monotherapy in pediatric patients with peanut allergy [Internet]. ClinicalTrials.gov; [cited 2023 Sep 25]. Available from: https://clinicaltrials.gov/ct2/show/NCT03793608

[63] Study in pediatric subjects with peanut allergy to evaluate efficacy and safety of dupilumab as adjunct to AR101 (peanut oral immunotherapy) [Internet]. ClinicalTrials.gov; [cited 2023 Sep 25]. Available from: https://clinicaltrials.gov/ct2/show/NCT03682770

[64] Clinical study using biologics to improve multi OIT outcomes (COMBINE) [Internet]. ClinicalTrials.gov; [cited 2023 Sep 25]. Available from: https://clinicaltrials.gov/ct2/show/NCT03679676

[65] Dupilumab and milk OIT for the treatment of cow’s milk allergy [Internet]. ClinicalTrials.gov; [cited 2023 Sep 25]. Available from: https://ClinicalTrials.gov/show/NCT04148352

[66] Bagnasco D, Ferrando M, Varricchi G, Puggioni F, Passalacqua G, Canonica GW. Anti-interleukin 5 (IL-5) and IL-5Ra biological drugs: efficacy, safety, and future perspectives in severe eosinophilic asthma. Front Med. 2017; 4: 135.

[67] Shik D, Tomar S, Lee JB, Chen CY, Smith A, Wang YH. IL-9-producing cells in the development of IgE-mediated food allergy. Semin Immunopathol. 2017; 39: 69-77.

[68] Lee JB, Chen CY, Liu B, Mugge L, Angkasekwinai P, Facchinetti V, et al. IL-25 and CD4⁺T_H2 cells enhance type 2 innate lymphoid cell-derived IL-13 production, which promotes IgE-mediated experimental food allergy . J Allergy Clin Immunol. 2016; 137: 1216-25.E5.

[69] Burton OT, Medina Tamayo J, Stranks AJ, Miller S, Koleoglou KJ, Weinberg EO, et al. IgE promotes type 2 innate lymphoid cells in murine food allergy. Clin Exp Allergy. 2018; 48: 288-96.

[70] Wilson JM, Li RC, McGowan EC. The role of food allergy in eosinophilic esophagitis. J Asthma Allergy. 2020; 13: 679-88.

[71] Khodoun MV, Tomar S, Tocker JE, Wang YH, Finkelman FD. Prevention of food allergy development and suppression of established food allergy by neutralization of thymic stromal lymphopoietin, IL-25, and IL-33. J Allergy Clin Immunol. 2018; 141: 171-9.E1.

[72] Horlick RA, King DJ, Mcknight AJ, inventors; AnaptysBio, Inc., assignee. Antibodies directed against interleukin-33 (IL-33) and methods of making and using. 10,059,764. 2018 Aug 28.

[73] Howard TD, Koppelman GH, Xu J, Zheng SL, Postma DS, Meyers DA, et al. Gene-gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma . Am J Hum Genet. 2002; 70: 230-6.

[74] Chiaramonte MG, Mentink-Kane M, Jacobson BA, Cheever AW, Whitters MJ, Goad ME, et al. Regulation and function of the interleukin 13 receptor α 2 during a T helper cell type 2-dominant immune response. J Exp Med. 2003; 197: 687-701.

[75] Chinthrajah S, Cao S, Liu C, Lyu SC, Sindher SB, Long A, et al. Phase 2a randomized, placebo-controlled study of anti-IL-33 in peanut allergy. JCI Insight. 2019; 4: e131347.

[76] Fiocchi A, Vickery BP, Wood RA. The use of biologics in food allergy. Clin Exp Allergy. 2021; 51: 1006-18.