AIT can be administered by the subcutaneous, sublingual, or oral routes. There is some evidence suggesting that the immune system can develop tolerance thanks to the action of regulatory T cells (Tregs). These T cells release ILs such as transforming growth factor β (TGF-β) and IL-10, leading to an immune deviation in favour of T-helper 1 (Th1) secreting interferon γ (IFN-γ) [1]. IL-10, TGF-β and IFN-γ exert inhibitory effects on Th2 cytokines, reducing the levels of IL-4 and IL-5 production with the result of suppressing Th2 and innate lymphoid cells type 2 (ILC-2s), as well as mast cells (MCs), eosinophils (Eos), and basophils (Bas), which are key players in allergic inflammation. In addition, IL-10, TGF-β, and IFN-γ induce a switch in the Ig class and promote the production of blocking antibodies, particularly IgG4, which compete with specific IgE for allergen binding [2].

The inhibition of allergen-specific IgE interactions by IgG4 limits cross-linking of high-affinity IgE receptors Fcε receptor I (FcεRI) on both MCs and Bas, lowering degranulation and avoiding anaphylaxis. Furthermore, IgG4 can also block low-affinity receptors (FcγRIIb) on B cells, thereby preventing IgE from facilitating allergen presentation to T cells.

The binding of allergen-specific IgE to IgE receptors (FcεRI) on Bas and MCs can lead to the release of inflammatory mediators and cause anaphylaxis. However, IgG4 can inhibit these interactions, thus preventing the cross-linking of high-affinity IgE receptors and reducing degranulation [2].

Another possible mechanism of action of AIT could be the inhibition of ILC-2s, which contribute to allergic inflammation by type 2 cytokine production after their activation by the epithelium-derived cytokines thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 [3].

mAbs effectively interfere with signaling pathways occurring subsequent to the activation of ILC-2, thereby contributing to mitigating inflammatory processes. A visual representation of the complex cellular and cytokine networks involved in allergic responses is provided in Figure 1, showing how mAbs can modulate these networks during allergen immunotherapy.

Omalizumab is proved to be effective in the treatment of severe allergic asthma and AR. The primary goals of using omalizumab during AIT are:

(1)

To permit AIT-mediated tolerance in patients who would not be able to increase allergen dosage during early build-up phase due to their significant immunoreactivity.

There is some evidence based on the findings of double-blind, placebo-controlled (DBPC) studies (see Table 1) [8–13] showing the effect of omalizumab used before and during AIT as an adjunctive treatment in patients with respiratory allergies (AR and bronchial asthma).

In 2009, Kopp et al. [10] evaluated the effects of the combination of omalizumab and AIT compared to AIT alone in 140 patients with AR and co-morbid seasonal allergic asthma. Results showed a reduction of AIT side effects during the build-up and/or maintenance phase, reduction of daily symptoms, improved control of rhinoconjunctivitis and asthma, and improvement in QoL. Other authors suggested that this combined therapy promotes a better effect on respiratory symptoms and a long-lasting tolerance to specific allergens [14].

Severe asthma currently represents a contraindication to AIT. However, a recent study by Bożek et al. [15] revealed that a combination of AIT targeting house dust mites (HDM) and omalizumab is more effective in reducing symptoms and decreasing the daily dose of inhaled corticosteroids (ICS) than omalizumab alone or AIT alone in patients with HDM-driven asthma. Another study conducted in a paediatric allergy unit by Valdesoiro-Navarrete et al. [13] showed that omalizumab was administered successfully and safely before the initiation of AIT to achieve asthma control and during the AIT build-up-maintenance phase. This combination therapy was effective in achieving asthma control and improving lung function and QoL compared to baseline values [13]. Thus, when AIT is contraindicated, omalizumab may allow patients to be treated safely with AIT. On the other hand, allergic reactions occurred in some other patients in whom this combined approach was used [16].

Since follow-up data are lacking in the majority of studies, it is unclear if omalizumab treatment is related to quicker and longer-lasting tolerance development [17].

A recent review by Pfützner and Schuppe [16] suggested the use of recombinant IgG antibodies directed against specific epitopes of an allergen: similar to the AIT-induced IgG antibodies, they can prevent allergens from binding to IgE antibodies.

The build-up and maintenance phases of Hymenoptera VIT are known to be characterised by recurrent adverse reactions that encompass local reactions at the injection site, as well as systemic allergic manifestations including generalized urticaria, angioedema, bronchospasm, and, in severe instances, anaphylaxis [18]. Antihistamines proved effective in preventing mild hypersensitivity reactions, but omalizumab pre-treatment has been proven effective in cases of recurrent severe adverse events that prevent reaching the full maintenance dose, particularly in those with MCs disorders (such as mastocytosis or MCs activation syndrome) [19].

A case report by Soriano Gomis et al. [20] showed that omalizumab pretreatment before starting bee-VIT was not effective in preventing recurrent anaphylactic events during the build-up phase.

However, in most studies, omalizumab showed efficacy in protecting high-risk patients from severe reactions during VIT and also in improving adherence to treatment. To our knowledge, 19 studies were published so far (Table 2) [20–38]. Most of them are case reports, from limited patient subsets, with different timings of administration and dosage; large randomised studies are currently lacking.

In 2017 Stretz et al. [31] published a retrospective case series on 10 patients, assessing the effectiveness of anti-IgE antibodies in combination with a high-maintenance dose of VIT in preventing severe adverse reactions among patients with a record of systemic allergic reactions to insect bites. The combination therapy was effective in reducing the frequency and severity of adverse reactions to immunotherapy. The study also reported a favourable safety profile; evidence suggests that omalizumab should be stopped when complete tolerance is reached for both VIT and stings and that VIT should eventually be continued for an adequate duration [39].

FA is characterised by an adverse immune-mediated response to a dietary protein. Unlike allergies to aeroallergens and Hymenoptera venoms, foods AIT (known as OIT) are still an experimental treatment and only a formulation for peanut allergy was approved in children and adolescents [40]. Hypersensitivity reactions occur significantly more frequently than in respiratory and Hymenoptera venom allergies, leading to AIT discontinuation [41].

In a recent meta-analysis by Chu et al. [42], the efficacy and safety of OIT as a treatment for peanut allergy were examined. The findings revealed that, although OIT effectively induces desensitization, it considerably increases the risk of allergic and anaphylactic reactions compared to avoidance or placebo [42]. Consequently, the authors emphasized the need for safer treatment approaches [42].

In a study conducted by Nadeau et al. [43] in 2011, representing the first phase I study, 11 children with cow’s milk allergy were treated with a combination of omalizumab and rapid oral milk desensitisation. Omalizumab was administered at a dose ranging from 150 mg to 300 mg for nine weeks prior to the start of rapid oral desensitisation. The build-up phase included weekly up-dosing over the next 7–11 weeks, while omalizumab was continued until the 16th week to reach a maximum milk dose of 2,000 mg. Nine patients were able to tolerate the maximum dose, and desensitization was maintained in all patients with continuous milk administration after the discontinuation of omalizumab. Since then, several clinical trials have been conducted on the use of anti-IgE mAbs in combination with OIT for peanut, egg, milk, and multiple allergens, resulting in safe and effective rapid desensitisation with high maintenance rates, as reported in Table 3 [43–54].

The data consistently demonstrates effectiveness in accelerating the desensitization process [43–47]. One notable study by Sindher et al. [51] has provided substantial evidence supporting the benefits of combining omalizumab with AIT. Their research indicates that the administration of fixed-dose omalizumab alongside OIT induces early changes in the ratio of IgG4/IgE [51]. This alteration is a crucial marker for immune tolerance and serves as an indicator of the desensitization process.

Recent studies have investigated the feasibility of sustained long-term desensitisation thanks to omalizumab in patients with FAs. Andorf et al. [50] conducted a 5-year follow-up observational study on 34 patients, using rapid desensitisation facilitated by omalizumab. A number of participants in the study had their long-term maintenance dosage lowered after achieving the maintenance dose of 2 g of protein for their respective allergens. At the end of the follow-up, each patient passed the 2 g oral food challenge (OFC), demonstrating the persistence of desensitization.

Omalizumab has been observed to prevent adverse events as well as facilitate high-dose desensitisation when used in combination with OIT. In fact, in a recent meta-analysis of randomised and non-randomised observational studies, the addition of omalizumab to different OITs showed a faster dose increase, high-dose desensitisation, higher maintenance doses of immunotherapy, and a positive impact on the QoL of patients and caregivers [55].

The omalizumab as Monotherapy and as Adjunct Therapy to Multi-Allergen OIT in Food Allergic Participants study (OUtMATCH; NCT03881696), focuses on patients who have multiple FAs and aims to evaluate the efficacy of omalizumab as both monotherapy and as an adjunct to OIT [52]. Participants aged from 1 year to 55 years with an allergy to peanuts and at least two of the following foods will be included: cashew, hazelnut, walnut, milk, egg, and wheat. The study consists of three stages and the primary outcome is tolerance of a single dose of > 600 mg peanut (cumulative > 1,044 mg). Secondary outcomes include tolerance to other allergens and QoL.

Omalizumab is the only mAb approved to date, but the optimal dosage remains unclear. Recent studies suggest that doses should be adjusted based on body weight alone, irrespective of total IgE levels. However, increased local reactions cannot be usually prevented, and AIT-related anaphylaxis cannot be completely ruled out by omalizumab treatment.

In this context, the potential of newer developments and preparations like the anti-IgE antibodies ligelizumab and quilizumab (which are capable of depleting IgE-bearing plasmablasts and B cells) may be of particular interest [56–58].

A clinical trial (NCT04984876) is underway to investigate the efficacy and safety of ligelizumab as monotherapy for patients with peanut allergy [53]. This trial is open to participants aged from 6 years to 55 years, who have a peanut allergy. Participants will receive either ligelizumab or a placebo for 52 weeks, with the primary outcome of determining the ability to tolerate a single dose > 600 mg (cumulative > 1,044 mg) of peanut protein by week 12. Key secondary outcomes will include the ability to tolerate higher doses of peanut (> 1,000 mg or > 3,000 mg) at weeks 12 and 52, as well as measuring the QoL of participants.

In a study conducted on 103 patients suffering from grass pollen-induced seasonal AR, the patients were assigned to four groups namely SCIT, dupilumab, SCIT + dupilumab, or placebo in a randomised 1:1:1:1 manner [60]. The study was a phase 2a multicenter, DBPC, parallel-group study; investigators noted that administering SCIT together with dupilumab for 16 weeks increased SCIT tolerability but did not result in any significant improvement in nasal symptom scores when compared to SCIT alone [60]. It is worth noting, however, that this study was of short duration, and further research is required to determine the long-term safety and effectiveness of using dupilumab in combination with SCIT for the treatment of AR.

Dupilumab’s efficacy and safety as an OIT adjuvant therapy and as a monotherapy in FA are being examined in different ongoing studies.

In the first case study reported by Rial et al. [61], a 30-year-old woman affected by a severe form of atopic dermatitis and corn and nuts allergy was treated with dupilumab, leading to desensitization after three months of treatment. A confirmatory OFC was conducted to assess the patient’s reaction to corn and nuts.

The efficacy of dupilumab as a monotherapy in children between the age of 6 and 17 is the subject of a study that started in 2019 [62]. The aim of this study is to estimate the percentage of children who can tolerate peanuts in a food challenge after 24 weeks of treatment with dupilumab [62].

Another study is assessing whether dupilumab might improve the proportion of children who tolerate an oral peanut challenge after completing peanut OIT [63]. The study additionally evaluates whether dupilumab has the potential to improve the safety and tolerability of peanut OIT and whether long-term use of dupilumab after achieving maintenance gives further benefits in comparison with short-term use until the maintenance dose is reached [63].

In addition, there is an RCT in phase 2 examining the efficacy of dupilumab in enabling immunotherapy for patients with a history of multiple FAs, including peanuts [64].

Another phase 2 RCT is investigating dupilumab as a supplement to milk OIT. Patients in the treatment arm will receive dupilumab before and during the milk OIT updosing phase, followed by eight weeks of milk OIT without dupilumab. The proportion of patients who can tolerate at least 2,040 mg of cumulative cow’s milk protein will be evaluated at week 18 [65].

For a complete list of ongoing studies investigating the use of dupilumab in combination with allergen immunotherapy, refer to Table 4.

The use of biologics targeting upstream alarmins, such as IL-25, IL-33, and TSLP, is an additional approach to the treatment of allergic diseases.

Increased levels of IL-4, IL-5, and IL-13 can be observed as a consequence of alarmins’ combined actions, which leads to a downstream transition from a tolerant Th1-dominant state to a pro-allergic Th2 response. Alarmins are crucial for triggering and maintaining FA since they are a key factor in the Th2 response. According to a mouse model, blocking TSLP, IL-25, and IL-33 with mAbs has the potential to prevent the development of FA [71].

A humanised IgG1/kappa mAb named etokimab was developed specifically to bind IL-33 and neutralize its biological impact [72]. IL-33 is a versatile cytokine that contributes significantly to the onset and progression of several medical conditions. Its actions are dual, as it behaves both as an alarmin in response to signs of tissue damage while also prompting the production of IL-5 and IL-13 by ILC-2, thus stimulating Th2 immune responses. In turn, these two cytokines inhibit the growth of Tregs in favour of Th2 differentiation and MCs activation [73, 74].

In a DBPC phase 2a trial for adults with peanut allergy, a single administration of etokimab significantly increased desensitization to peanut protein in the active group, with reduced skin prick test (SPT) wheal size and peanut-specific IgE after 14 days [75]. Compared with the placebo, the etokimab group experienced fewer adverse events. The clinical result correlated with a reduction of IL-4, IL-5, IL-9, and IL-13 in CD4⁺ T cells.

No clinical trials on tezepelumab, a TSLP antagonist, in FA are being conducted at the moment [76].

Currently, the use of biological agents against IL-25 in humans has not been investigated.