Omalizumab, a humanized anti-IgE monoclonal antibody, is currently recommended as add-on therapy for patients six years of age and older with severe allergic asthma [49]. By binding to circulating IgE, omalizumab prevents IgE from engaging its high-affinity receptor, FcεRI, on the surface of basophils and mast cells, which degranulate when antigen cross-links neighboring IgE-FcεRI complexes [50, 51]. When basophils and mast cells are prevented from degranulating, many of the deleterious mediators, including cytokines, histamine, leukotrienes, and proteases, which promote allergic inflammation, fail to enter the extracellular milieu [51, 52].

In 2019, Oliveira et al. [53] reported that obese individuals with severe asthma administered omalizumab every two to four weeks over a twelve-month period exhibited significant improvement in lung function [i.e., forced expiratory volume in one second (FEV₁)] and asthma control. The administration of omalizumab also decreased the number of asthma exacerbations and the prescribed dose of inhaled corticosteroids. As compared to placebo, Geng et al. [54] demonstrated that omalizumab essentially had the same effects in obese individuals with moderate-to-severe allergic asthma as those of Oliveira et al. [53]. In contrast, Sposato et al. [55] reported that obesity reduced the effectiveness of omalizumab in severe allergic asthmatics while Gibson et al. [56] revealed that it was significantly more probable that obese as compared to non-obese allergic asthmatics would be classified as non-responders to omalizumab. Although typically reserved for severe allergic asthma, administration of omalizumab to non-atopic asthmatics, the majority of whom were obese, reduced emergency room visits, hospitalizations, and corticosteroid use [57]. Thus, omalizumab could become a viable controller medication for select non-atopic obese asthmatics, yet more rigorous studies are needed.

To independently initiate signal transduction and consequently sequelae of atopic inflammation via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, interleukin (IL)-4 and IL-13, which are T_H2 cytokines, utilize, in part, the IL-4 receptor subunit alpha (IL-4Rα) [58]. Specifically, IL-4 signals via the type I IL-4 receptor (IL-4R) complex, which is a heterodimer consisting of IL-4Rα and the cytokine receptor common subunit gamma (γc) while IL-13 signals via the type II IL-4R complex, which is also a heterodimer but consists of IL-4Rα and the IL-13 receptor subunit alpha-1 (IL-13Rα1) [58]. IL-4 is required for the differentiation of T _H2 cells, suppression of T regulatory (T_reg) cells, IgE production in B cells, and adhesion of eosinophils to the walls of blood vessels while IL-13 induces airway smooth muscle contraction and proliferation and increases expression of FcεRI on the surface of mast cells, eotaxin and mucin in bronchial epithelial cells, and IgE in B cells [59–61]. Following antigen sensitization and challenge, Dahm et al. [62] demonstrated that bronchoalveolar lavage (BAL) IL-4 and IL-13 were significantly greater in mice obese because of a genetic deficiency in carboxypeptidase E (Cpe^fat mice) as compared to lean wild-type mice. However, in human subjects, neither sputum IL-4 nor IL-13 messenger ribonucleic acid (mRNA) expression were different between lean and obese asthmatics [63].

Dupilumab, a human I gG₄ monoclonal antibody, antagonizes IL-4 and IL-13 signal transduction by binding to IL-4Rα, which is expressed by hematopoietic and non-hematopoietic cells [64, 65]. According to the Global Initiative for Asthma [49], dupilumab is recommended as add-on therapy for (1) individuals who are six years of age and older with severe eosinophilic/T_H2-high asthma or (2) adolescents and adults that require maintenance treatment with oral corticosteroids. Presently, preliminary data exists from one randomized, double blind, placebo-controlled study in which investigators examined the impact of BMI on the effectiveness of dupilumab in a cohort of patients with uncontrolled, moderate-to-severe asthma [66, 67]. Specifically, regardless of BMI, dupilumab, as compared to placebo, significantly improved FEV₁ and decreased the annualized rate of severe asthma exacerbations.

The biological response to inhaled asthma stimuli, including air pollutants, antigens, and viruses, is partially characterized by secretion of IL-5, a T _H2 cytokine, from T _H2 lymphocytes and/or group 2 innate lymphoid cells (ILC2) (Fig. 1) [68–70]. Once released into the extracellular space, IL-5 can bind the IL-5 receptor subunit alpha (IL-5Rα) on the surface of eosinophils, an event that facilitates interaction with the cytokine receptor common subunit beta (βc), which subsequently leads to eosinophilopoiesis and eosinophil maturation and survival [70, 71]. In asthma, eosinophils drive AHR, mucus production, tissue injury, and airway remodeling [72]. Since sputum IL-5 and submucosal eosinophils are greater in obese as compared to lean asthmatic human subjects [63, 73], it is reasonable to speculate that currently available monoclonal antibodies directed against either IL-5 (mepolizumab and reslizumab) or IL-5Rα (benralizumab) for severe eosinophilic asthma could be beneficial add-on therapy for obese asthmatics [49, 74].

In a post-hoc meta-analysis, Albers et al. [75] reported that regardless of BMI mepolizumab as compared to placebo (1) decreased blood eosinophil counts and the annual rate of asthma exacerbations and (2) increased asthma control and pre-bronchodilator FEV₁ in patients twelve years of age and older with severe eosinophilic asthma. Consistent with Albers et al. [75], preliminary data from Da Cunha et al. [76] demonstrated that mepolizumab administration over a twelve-month period effectively decreased blood eosinophil counts and the number of asthma exacerbations in eleven obese asthmatics.

To date, only preliminary data from clinical trials evaluating the effectiveness of benralizumab in obese asthmatics has been made publicly available, and the authors of these reports demonstrate that benralizumab is less effective in obese as compared to non-obese asthmatics. In the first study, a post-hoc pooled analysis of data extracted from the SIROCCO and CALIMA clinical trials was performed, and as compared to placebo, subcutaneous administration of benralizumab to obese adults with severe, uncontrolled eosinophilic asthma numerically caused (1) an improvement in pre-bronchodilator F EV₁ and (2) a reduction in the number of asthma exacerbations [77–79]. However, in this same study, benralizumab significantly improved FEV₁ and decreased the number of asthma exacerbations in normal/underweight and overweight asthmatics [78]. In the second study, Nanzer et al. [80] reported that obesity impaired the beneficial effects of benralizumab in patients with severe eosinophilic asthma. Taken together, it is unclear if benralizumab significantly improves lung function and asthma control in obese asthmatics. Nevertheless, these data certainly provide a strong rationale to pursue further clinical trials evaluating the efficacy of benralizumab in obese individuals with severe eosinophilic asthma.

Brodalumab is a human IgG₂ monoclonal antibody with a high affinity for IL-17 receptor A (IL-17RA), which is used, in part, by IL-25 in addition to IL-17A, IL-17C, IL-17F, and the IL-17A/F heterodimer to transduce intracellular signals [85, 86] Although currently approved to treat moderate-to-severe plaque psoriasis that is refractory to other therapies [85], Busse et al. [86] executed a phase 2a, randomized, double-blind, placebo-controlled, clinical trial to assess the effectiveness of brodalumab as a treatment for moderate-to-severe asthma. However, as compared to placebo, brodalumab did not improve lung function or symptoms scores in the full study population. In a separate interventional clinical trial, brodalumab demonstrated no efficacy on asthma control in adult asthmatics specifically exhibiting high bronchodilator reversibility [87]. Of importance, subjects in neither study were recruited according to BMI status. Thus, given that IL-17A and IL-25, which both use, in part, IL-17RA to exert their biological effects, are significantly greater in sputum of obese as compared to non-obese asthmatics [63], future studies focusing on the effectiveness of brodalumab in obese asthma is warranted.

Itepekimab is an IgG_4P monoclonal antibody against IL-33, and in 2021, Wechsler et al. [88] reported the results of a phase 2 clinical trial evaluating the effectiveness of itepekimab in the treatment of moderate-to-severe asthma. As compared to placebo, itepekimab monotherapy significantly improved asthma control and pre-bronchodilator FEV₁. Nevertheless, the investigators did not specifically examine the impact of BMI on the effectiveness of itepekimab. The efficacy of astegolimab, a human IgG₂ monoclonal antibody directed against ST2, was assessed for the treatment of severe asthma in a phase 2b, randomized, placebocontrolled, double-blind clinical trial in which thirty-six percent of the patients had a BMI greater than 30 kg/m² [89]. Over the fifty-two-week trial, astegolimab, when compared to placebo, improved quality of life and reduced the number of asthma exacerbations only in participants with low numbers of blood eosinophils. Although thirty-six percent of subjects in this trial were obese, the investigators did not specifically examine the effectiveness of astegolimab in their obese patients. Thus, it is of interest to determine the specificity of astegolimab in the treatment of obese asthma with neutrophilic inflammation given the effectiveness of an anti-ST2 antibody in a mouse model of obese asthma that is dominated by neutrophils [69].

To initiate intracellular signaling, TSLP requires a heterodimeric receptor complex consisting of cytokine receptor-like factor 2 (CRLF2 or TSLPR) and the IL-7 receptor subunit alpha (IL-7Rα) [90]. Tezepelumab, a human monoclonal anti-TSLP antibody, is indicated as add-on treatment for individuals twelve years of age and older with severe asthma [49, 91]. To exert its beneficial effects, tezepelumab binds free TSLP, which is then prevented from subsequently binding TSLPR [91]. Preliminary data extracted from the DESTINATION, NAVIGATOR, and PATHWAY clinical trials illustrate that, regardless of an asthmatic’s baseline BMI, tezepelumab administration reduced the annualized asthma exacerbation rate [92–96]. Thus, this is promising evidence that the newest asthma controller medication, tezepelumab, may be effective in obese asthmatics.

IL-17A, an extensively studied pro-inflammatory cytokine, is produced by a plethora of cells, including T_H17, γδ T, invariant natural killer T, lymphoid-tissue inducer-like, and Paneth cells as well as ILC3 [97, 98]. Engagement of an IL-17A homodimer or an IL-17A/F heterodimer with the IL-17 receptor complex, which consists of IL-17RA and IL-17RC, leads to increased expression of neutrophil chemotactic cytokines, granulopoiesis factors, acute phase proteins, and pro-inflammatory cytokines such as IL-1β and TNF-α [99]. Sputum IL-17A is greater in obese as compared to non-obese asthmatics while neutralization of IL-17A in genetically obese mice reduced O ₃-induced increases in airway responsiveness in addition to BAL keratinocyte chemoattractant (KC) and neutrophils [63, 100].

A single clinical trial evaluating the effectiveness of secukinumab, an anti-IL-17A human IgG₁κ monoclonal antibody, in poorly controlled asthma was terminated prior to completion with the caveat that future clinical trials involving this biologic require an extensive overhaul, including modifications to the study design, endpoints, and population as well as the use of a different anti-IL-17A antibody [101, 102]. Thus, if further clinical trials with secukinumab are executed in asthmatics, it would be crucial to stratify subjects via BMI given the previously aforementioned human and animal subject data concerning the potential importance of IL-17A in obese asthma [63, 100].

The deleterious effects of TNF-α in inflammatory diseases, including asthma and obesity, are well established [103–105]. Obesity increases serum TNF-α in both humans and mice [106, 107], and a polymorphism in the promoter region of the human gene (TNF), which leads to increased TNF expression, is coupled to a stronger association of obesity with asthma, particularly non-atopic asthma [108, 109]. However, in obese mice genetically deficient in TNF-α, the severity of increases in airway responsiveness induced by O₃ were enhanced, which implies a protective effect of TNF-α in this animal model of non-atopic asthma [110]. In contrast, Kim et al. [111] reported that neutralization of TNF-α with a polyclonal antibody decreased airway responsiveness in antigen sensitized and challenged mice. Consistent with the results from pre-clinical animal studies, the effectiveness of etanercept, a humanized soluble TNF receptor fusion protein that neutralizes the effects of TNF-α, has been inconsistent in the treatment of asthma [112]. For example, in an open label uncontrolled clinical study involving fifteen patients, Howarth et al. [113], despite demonstrating that etanercept significantly improved lung function and decreased asthma symptoms and airway responsiveness, reported that etanercept paradoxically led to asthma exacerbations and respiratory tract infections in 52.9 and 58.8% of participants, respectively. In a randomized, double-blind, placebo-controlled clinical trial, etanercept failed to improve pre-bronchodilator FEV₁, quality of life, or asthma control in adults with moderate-to-persistent asthma [114]. Finally, Berry et al. [115] reported, as compared to placebo, that subcutaneous administration of etanercept twice weekly over a ten-week period, reduced responsiveness to methacholine, increased pre-bronchodilator FEV₁, and improved quality of life. It is important to note that none of these studies stratified patients by BMI. If, in the future, studies are designed to specifically evaluate the efficacy of etanercept in obese asthma, caution must be taken since anti-TNF-α therapy is associated with statistically significant weight gain [116].

IL-23, a member of the IL-12 family of cytokines, consists of two subunits, IL-12p40, which it shares with IL-12, and IL-23p19, and is secreted by activated dendritic cells and macrophages (Fig. 1) [117, 118]. The biological effects exerted by IL-23, including differentiation of naïve T cells to T_H17 cells, proliferation and survival of T_H17 cells, and stimulation of IL-17A release from T _H17 cells, manifest following engagement of IL-23 with its receptor, which also consists of two subunits [IL-12 receptor subunit beta-1 (IL-12Rβ1) and IL-23 receptor (IL-23R)] [119–122]. Obesity and asthma, independently, increase serum IL-23 in human subjects [123, 124], BAL IL-23 is increased to a greater extent in obese as compared to lean mice following exposure to O ₃ [100], and inhibition of IL-17A, whose expression can be induced by IL-23, reduces increases in airway responsiveness and BAL KC and neutrophils induced by acute exposure to O₃ [100, 125]. Contrary to this evidence supporting a role for IL-23 in the pathogenesis of obese asthma, Brightling et al. [126] reported that, as compared to placebo, administration of risankizumab, a humanized I gG₁ monoclonal antibody, which binds to the p19 subunit of IL-23, decreased the time to the first asthma worsening after treatment commenced, increased the annualized rate of asthma worsening, and had no effect on FEV₁ or sputum eosinophils or neutrophils [127]. A subgroup analysis of the participants stratified by BMI also revealed that risankizumab was ineffective, as compared to placebo, at lengthening the time to the first asthma worsening [126].