Allergen Immunotherapy and Biologics

Allergen immunotherapy (AIT) remains the only disease-modifying treatment for IgE-mediated disorders. The combination of AIT with biologic agents represents a promising therapeutic approach, offering enhanced efficacy, safety and clinical outcomes in the management of severe allergic conditions such as food allergy, asthma, rhinitis and hymenoptera venom allergy. Notably, existing evidence in pediatric populations predominantly focuses on omalizumab. However, there are no standardized protocols for the combined use of AIT and biological drugs.

INTRODUCTION

Allergen immunotherapy (AIT) is the only treatment capable of modifying immunoglobulin (Ig) E-mediated diseases by inducing immune tolerance through the gradual exposure of patients to increasing amounts of allergens. AIT initially reduces the activation of mast cells and basophils and subsequently promotes the expansion of regulatory B, T, and dendritic cells, which secrete anti-inflammatory cytokines [interleukins (IL)-10, transforming growth factor beta (TGF β)]. This process leads to the suppression of allergic inflammation and the production of blocking antibodies (IgG4, IgG1, IgA), which prevent IgE-allergen binding and promote a switch from a type 2 to a type 1 immune response ¹. However, AIT may be associated with a risk of allergic reactions and, in some cases, can lead to a worsening of respiratory symptoms in patients with asthma and/or allergic rhinitis ². For this reason, some patients may not adequately tolerate AIT alone. Recent studies have indicated that biologic agents can act as adjuvants to AIT in the treatment of allergic diseases, improving symptom control while simultaneously reducing the onset of adverse reactions ³.

Biologics modulate key immunological pathways implicated in allergic responses, involving IgE, IL-4, IL-13 and alarmins such as thymic stromal lymphopoietin (TSLP), IL-33 and IL-25 ⁴. Consequently, the combination of AIT and biologics in patients with severe allergic diseases has emerged as a promising therapeutic approach. While biologic agents provide rapid symptom relief and help prevent further exacerbations, AIT addresses the root cause of allergic disease by inducing long-term immune tolerance. This integrated strategy not only enhances the safety and tolerability of the desensitization process, but also contributes to improved clinical outcomes ⁵.

FOOD ALLERGY

Combining biologics with oral immunotherapy (OIT) may represent a suitable therapeutic option for patients with multiple food allergies (MFA), a history of severe allergic reactions (even to small quantities of allergens) and significant comorbidities. Several studies indicate that omalizumab (monoclonal antibody anti-IgE, OMA) combined with OIT (OMA + OIT) improves the threshold for allergen(s) reactivity and may reduce the severity of the allergic reaction. Furthermore, this approach has the potential to facilitate a more rapid dose escalation, allows high-dose desensitization, and supports higher maintenance doses during OIT. These results underscore the beneficial effects of OMA + OIT on quality of life for both patients and caregivers ². OMA has been approved for use in food allergy in the USA, thanks to FDA (Food and Drug Administration) approval following the results of the OUTMATCH study. This multicentre randomized trial enrolled patients (1 to 55 years of age) who were allergic to peanuts and at least two more foods (among milk, egg, wheat, cashew, hazelnut, walnut). Patients were randomized (2:1 ratio) to receive either OMA (dose calculated according to IgE concentration and weight) or placebo, administered subcutaneously every 2 to 4 weeks over a period of 16 to 20 weeks. After this phase an oral food challenge was repeated: 67% of participants treated with OMA tolerated at least 600 mg of peanut protein, compared to 7% of the placebo group. A higher percentage of patients treated with OMA achieved tolerance to at least 1000 mg of cashew, egg, and milk compared to those not treated with the biologic drug ⁶. Additional studies have also shown the positive effects of OMA + OIT in MFA ^5,6. Similar results were found in studies on patients with single food allergy ⁷. Uncertainty remains about the optimal therapeutic period and the minimum effective dose of OMA ⁷. Regarding the optimal time to start biological therapy and its correct duration, a meta-analysis highlighted that starting OMA at least 4 weeks prior to OIT and continuing it for 20-24 weeks after reaching maintenance dose enhances safety and efficacy ⁷. Moreover, the MIMIX study compared an OMA course of 3 doses of 150 mg every 4 weeks in combination with high or low doses of multi-allergen OIT (2-5 allergens). Both groups showed an increase in the sIgG4/sIgE ratio ≥ 25% compared to baseline for at least two foods after 18 weeks, with no significant differences ⁴. Therefore, low maintenance doses of OIT may be sufficient to achieve food tolerance if preceded by a short course of biological therapy. However, further research is needed to confirm this data ⁵.

In addition, the BOOM study is evaluating two OMA dosing regimens (16 and 8 mg/kg per month, respectively) to determine the optimal dosage for reaching the maintenance OIT dose more quickly ^4,8. It remains an open question as to what happens after OMA discontinuation in MFA. In the OUTMATCH phase 3 study, 60 patients, after completing a 24-week OMA extension, were asked to choose between continuing food avoidance, repeating rescue OIT, or maintaining dietary consumption (DC, defined by a minimum of 300 mg of the reintroduced protein daily over one year). The choice depended on the results of the final oral food challenge and on the option the patient preferred. Most were able to introduce allergenic foods into their diet, especially milk, egg and wheat compared to nuts and peanuts and to maintain the introduction after discontinuing OMA. Some adverse events (in particular, 5 episodes of anaphylaxis) occurred in subjects who had achieved DC, while some participants returned to avoidance due to the onset of mild symptoms related to reintroduction, but also for personal taste or food aversion ⁶. Despite promising results, patients undergoing treatment with OMA + OIT are still advised to take necessary precautions, including always carrying a self-injectable epinephrine device ⁸.

Regarding other biologic therapies, dupilumab (anti IL-4/IL-13 monoclonal antibody) has shown potential in management of food allergy. It has been associated with significant reductions in specific IgE levels and may protect against the development of new food allergy. A meta-analysis investigated the progression of the atopic march in patients with moderate-severe atopic dermatitis treated with dupilumab, showing a significant reduction in the risk of worsening pre-existing food allergies ⁹. In addition, a phase 2 clinical trial (NCT03682770) demonstrated that the combination of dupilumab with peanut OIT may enhance OIT efficacy during the dose escalation phase ¹⁰.

Regarding safety of biologics in food allergy, systematic evidence in the literature highlights only mild or moderate adverse effects. However, there are still limited data on long-term use and safety ¹¹.

ASTHMA AND RHINITIS

Most of the available research on combining AIT with biologic treatments for severe allergic asthma and rhinitis mainly focuses on OMA in the paediatric population ⁵. The efficacy and safety of OMA have been supported in a retrospective study conducted by Shen et al., which involved 120 children with moderate to severe allergic asthma. Patients were divided into three groups, each receiving a different treatment: subcutaneous immunotherapy (SCIT), omalizumab, or a combination of both SCIT and OMA. The results revealed that combination therapy group achieved greater improvements not only in asthma control, as measured by the Childhood Asthma Control Test (C-ACT) and Asthma Control Test (ACT), but also in control of symptoms related to allergic rhinitis as assessed by a Visual Analog Scale (VAS), along with lower fractional exhaled nitric oxide (FeNO) levels, and improved forced expiratory volume in one second (FEV₁) compared to the SCIT group. Notably, the improvement in FEV₁ was also greater in the combination therapy group than in those receiving OMA as monotherapy ³.

In their comprehensive meta-analysis, Guan et al. examined 9 high-quality randomized controlled trials, of which 5 targeted pediatric and adolescent patients suffering from seasonal allergic rhinitis and/or allergic asthma. The trials evaluated the efficacy and safety of AIT + OMA, compared to AIT alone, OMA monotherapy, and placebo. The results revealed that combination of AIT and OMA was significantly more effective than placebo. Furthermore, the use of OMA + AIT significantly improved control of rhinitis symptoms without an increased incidence of systemic adverse reactions. Currently, there is no evidence supporting the efficacy of other biologic treatments combined with AIT for asthma.

HYMENOPTERA VENOM ALLERGY

The available clinical evidence, largely from case reports and small case series, supports the use of OMA in combination with venom immunotherapy (VIT), before and during the induction phase, as well as throughout the maintenance phase, in individuals at high risk of systemic reaction recurrence. OMA demonstrated clinical efficacy in 3 pediatric patients with honeybee venom allergy and comorbid asthma. In these cases, a short course of OMA before starting a second rush protocol for honeybee VIT has been shown to effectively prevent the recurrence of systemic reactions experienced during previous VIT attempts. Furthermore, two of the three children successfully tolerated re-stings without any adverse reactions, indicating sustained VIT efficacy even following OMA discontinuation. To date, no further studies are available regarding the use of other biologic agents in combination with VIT for the treatment of hymenoptera venom allergy ¹³.

CONCLUSIONS

Patients with severe IgE-mediated allergies may benefit from the combination of AIT and biologics to reduce the risk of severe adverse reactions during AIT and to improve treatment adherence. In particular, biologic agents enhance the safety and tolerability of AIT by stabilizing mast cells and attenuating IgE-mediated hypersensitivity responses, reducing the incidence and the severity of adverse reactions and improving clinical outcomes. However, more data are required to develop well-defined and standardized protocols for this combined approach.

Acknowledgements

The authors have no acknowledgements to declare.

Ethical consideration

This manuscript is a narrative mini review and did not involve any original studies with human participants or animals conducted by the authors. As such, ethical approval was not required.

Funding

The authors have no fundings to declare.

Conflicts of interest statement

The authors declare no potential conflicts of interest with respect to the research, authorship, or publication of this article. No funding sources influenced the study design, data collection, analysis, interpretation, or writing of the manuscript.

Author’s contributions

MAT and RO designed the study and supervised; MN and CT revised the paper; CF and VM drafted the manuscript, with all authors. All authors approved the final version.

History

Received: September 16, 2025

Published: January 23, 2026