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Increased global prevalence of IgE-mediated allergies has led to increased morbidity. IgE-mediated allergies are caused by exposure to specific allergens in foods, pollen, mold, animals, insects, and others. Allergic diseases include allergic rhinitis, allergic asthma, atopic dermatitis, food allergy, and allergic rhinoconjunctivitis. Reactions can bemild to severe. In some cases, like in thosewith cat allergies, systemic reactions leading to status asthmaticus or anaphylaxis, potentially lifethreatening conditions, can occur. Pharmacotherapy to prevent and treat symptoms typically includes antihistamines, b2-agonists, topical corticosteroids, mast cell stabilizers, and leukotriene inhibitors. At the current time, allergen immunotherapy (AIT) is the only diseasemodifying treatment that alters the course of immune response, with benefitsoftenobservedevenaftercessationof therapy(1),butnowthere could be a new approach on the horizon. Thework by Shamji and colleagues (pp. 23–33) in this issue of the Journal (2), and the 2018 study by Orengo and colleagues (3), report successful AIT for cat allergy and potentially, if verified by larger trials, could lead toamajor leap forward forAIT.Allergensused for cat allergy AIT, both sublingual and subcutaneous, have progressed from crude extracts to sophisticated and targeted allergens. Crude cat allergen extracts were used for AIT through the mid-1990s (4); subsequent studies used extracts of Fel d 1 or recombinant Fel d 1, the major cat allergen (5). Overall, although some cat AIT studies with crude cat extracts or Fel d 1 have shown promising results in total rhinoconjunctivitis symptom scores, peak expiratory flow rate responses, medication scores, or allergen-specific or nonspecific bronchialprovocationtests,othershavefoundnosignificantdifferences betweenplaceboandactivegroups(4).Morerecentstudieshaveusedan equimolarmixture of seven short synthetic peptides that corresponded tomajorT-cell epitopes,whichwerederived fromtheprimarysequence of themajor cat allergen Fel d 1 (Cat-PAD) (6). Although initial studies usingCat-PADforcatallergyshowedbenefits, a larger2016phase3trial showednodifferencebetween theplaceboandactivegroup in themean combined score (combined total rhinoconjunctivitis symptom scores and rescuemedication use score) (7). Safety data for catAIT are limited because of the lack of high-quality placebo-controlled trials; however, reports of reactions requiring epinephrine have been reported (8). AIT may benefit those in whom allergies are not well controlled by pharmacotherapy or those who are monosensitized to Fel d 1. The studybyShamji andcolleagues in this issueof the Journaluses anovel approach toAIT.Acommon immunological response toAIT is an increase in allergen-specific IgG. Studieswith aeroallergens and food allergenshave indicated that desensitizationwithAIT is associatedwith increasedIgG/IgE.Thecurrenthypothesis is thatIgGcompeteswithIgE for allergenbinding, therebydecreasing IgE-mediated allergic response (9). To test this hypothesis, Orengo and colleagues developed two monoclonal IgGantibodies against Fel d 1 (REGN1908-1909) that bind simultaneouslyandnoncompetitively toconformational epitopesofFel d 1. They conducted a phase 1b, randomized, double-blind, placebocontrolled proof-of-mechanism study. Patients with cat allergy were administered a single subcutaneous dose of REGN1908-1909 (n=36) or placebo (n=37). Nasal allergen challenges were conducted at baseline and at Days 8, 29, 57, and 85 after treatment, and total nasal symptomscoreswere significantly reducedat all timepoints exceptDay 57. The study also found that REGN1908-1909 was well tolerated. A major benefit of the study was the rapid response from therapy, with benefits observed after a fewdays of prophylactic treatment rather than after many months of traditional AIT therapy. Furthermore, the positive clinical data was supported by mechanisticdata.Shamjiandcolleaguesevaluatedserumandnasalfluid frompatients treatedwith REGN1908-1909 and found that it inhibited allergen-IgE complex binding to B cells. Compared with control subjects, patients treated with REGN1908-1909 also had a reduced numberofcytokinesassociatedwith type2reactions (IL-4, IL-5,andIL13) as well as inflammatory markers (CCL17/TARC and CCL5/ RANTES).These studyresults lendsupport to themajorroleof theIgG/ IgE ratio in desensitization with AIT. This new approach to AIT could greatly add to the way we treat allergies.Typically, inAIT, theallergenisadministered(generallyorally, subcutaneously, or sublingually) with gradually increasing doses of the allergen over a period of time until the individual becomes desensitized (10). However, currently, whole foods or crude extracts of the allergen are often used, and there is great need for more U.S. Food and Drug Administration–approved AIT with regulation and standardization of the allergens. In the last fewdecades, great inroads inunderstanding the mechanisms underlying successful AIT have beenmade.Overall, there isashift fromaT-helpercell type2typeallergenic responsetoaT-helper cell type 1 tolerogenic response, leading to increased production of allergen-specific IgE,which interactswithhigh-affinityFceR1receptors on the surface ofmast cells andbasophils, priming these cells toward an allergic response on subsequent allergen encounters (11). These mechanistic insightshave further assistedwith thedevelopmentof safer andmore effective AIT therapies. Examples include the use of antiTSLP antibody, anti-IgE antibody, or anti IL-4Ra antibody in conjunction with AIT for allergy. Combining these monoclonal antibodies with AIT has been shown to significantly decrease the frequency and severity of reactions while decreasing the length of AIT from years tomonths (12). The use ofmonoclonal IgG antibodies (like thoseagainstFeld1[REGN1908-1909])offersadditionalbreakthrough approaches to inhibit and hopefully treat allergies. This is a promising area of research. Development of specific antiallergen IgG antibodies may potentially be a viable therapeutic This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern ([email protected]).