Type 2 T helper cell (Th2) inflammation is mediated by a group of cytokines termed “alarmins”, which include thymic stromal lymphopoietin (TSLP), interleukin (IL)-25 and IL-33. These alarmins serve as upstream signaling elements that are responsible for initiating Th2 immune responses by activating type 2 innate lymphoid cells (ILC2) and Th2 cells, leading to a cascade event resulting in the release of Th2 cytokines (IL-4, IL-5, IL-9, IL-13) and immunoglobulin (Ig)E, which manifests into an allergic inflammatory and autoimmune responses (1, 2).

IL-25 (also referred to as IL-17E) is one of the least studied alarmins, yet was first discovered over 20 years ago (3). It belongs to the IL-17 cytokine family that includes IL-17A to IL-17F. Unlike other members in the family, IL-25 binds to its receptor composed of IL-17 receptor A (IL-17RA) and IL-17 receptor B (IL-17RB) subunits to upregulate transcriptional factors such as NF-KB, STAT6, GATA3 and NF-ATC1, which active and polarize Th2 cells but not Th17 cells, resulting in the expression and secretion of IL-4, IL-5, IL-9 and IL-13 (reviewed in (4)). Upregulation of Th2 cytokines is involved in allergic inflammatory responses in the lungs, epithelial cells and the digestive tract (5, 6). Overall, IL-25 activation results in eosinophilia, in part by delaying eosinophil apoptosis (7), and therefore contributes to eosinophil-driven inflammatory diseases, such as asthma. Moreover, elevated IL-17RB expression was found in lung tissues from asthmatic patients (8), driving the IL-25 effects in this condition.

In asthma, although inhaled corticosteroids (ICS) form the backbone of current therapies, an estimated 24% of patients still exhibit clinical symptoms and are not well-controlled with combinational therapy consisting of ICS and long-acting beta agonists, which could affect patient mortality and quality of life (9). Typical difficult -to-treat asthma is featured with Th2 initiated inflammation (10). Moreover, recent literature suggests that IL-25 was required for induction of allergic airway inflammation. IL-25 concentrations in sputum correlate with disease severity (11), and are associated with type 2 inflammatory response during virus-induced exacerbations (12), as well as with the allergic phenotype (13). As IL-17RB was highly expressed on Th2-related immune cells (Th2 cells, eosinophils, mast cells) (14), and its transcript level in Th2 cells is correlated to serum IgE level during allergic airway inflammation (15), it is not surprising that IL-25 could cooperate with allergen to synergistically induce expressions of MHC-II and co-stimulatory molecules on asthmatic eosinophils, as well as promoting Th2 differentiation of autologous naïve Th2 cells from allergic asthma patients (16). Together with other lung resident cells expressing IL-17RB, it is believed that IL-25 is highly contributed to the inflammation and lung damage via its direct action on lung endothelial cells, antigen presenting cells and Th2-related immune cells during asthma progression (8, 17–19). Therefore, blunting IL-25 activity is an attractive target for asthma treatment. This hypothesis had been tested and validated in experimental animal models of allergic asthma. Antibodies targeting IL-25 could suppress airway hyperresponsiveness (AHR), while the co-treatment with soluble IL-13 receptor α2 (decoy receptor for IL-13) or soluble IL-25 receptor (decoy receptor for IL-25) could synergistically reduce inflammatory cell infiltration, AHR and airway remodeling in allergen induced asthma animal models (20, 21). IL-25 knock-out mice also demonstrated decreased lung pathology during allergen sensitization (22). Moreover, a rare polymorphism in IL-17RB, the signaling receptor for IL-25, is associated with a reduced incidence of asthma (23). Although blockade to the IL-25 pathway is a validated therapeutic approach to asthma in pre-clinical studies, clinical application of targeting the IL-25 pathway is still lacking except a Phase I clinical trial of an IL-25 neutralizing antibody launched in 2023 (NCT05128409) (24).

SM17 is a humanized monoclonal antibody belonging to the IgG4 subtype. Its fragment, antigen binding (Fab) region targets the human IL-17RB. Blockade of IL-17RB by SM17 is expected to interfere with IL-25 signaling, subsequently reducing the Th2-mediated inflammatory response, such as a reduction in cytokine release and eosinophilia in patients. Pre-clinical studies demonstrated that SM17 selectively binds to human IL-17RB, leading to inhibition of alarmin-induced IL-5, IL-9 and IL-13 production, and restoration of Th2 immunity and skin pathology in an animal model of atopic dermatitis (AD) (25). In the current, non-clinical study, the therapeutic role of SM17 in allergic asthma was investigated using a HDM extract-induced mouse model. Lung pathology, inflammatory cell infiltration and cytokine release were all normalized upon SM17 treatment in the HDM model. These encouraging findings support clinical development of SM17 as therapeutic agent for asthma treatment. Therefore, a first-in-human (FIH), randomized, double-blind, placebo-controlled Phase I trial was conducted to evaluate the safety, tolerability, PK, PD and immunogenicity of a single and multiple IV doses of SM17 in healthy participants.

In presenting compelling evidence that SM17 can ameliorate lung histopathology and biomarkers in the current animal model, such as improvements in Th2 cytokines, lung collagen level and cell infiltration, this strengthens the potential of SM17 as an effective treatment for asthma. Together with the promising efficacies in AD (25), SM17 as a first-in-class IL-17RB-targeting monoclonal antibody, was decided to proceed into clinical development. In this Phase I study, SM17 was well tolerated following single IV doses from 2 mg to 1200 mg and multiple IV doses from 200 mg to 600 mg (Q2W) in healthy adults. There were no dose-dependent increases in the incidence of TEAEs. Overall, TEAEs were mild and transient in nature, with headache representing the most common TEAE in both study parts. There were no discontinuations due to drug-related TEAEs, and no deaths were reported. One case of SAE of clavicle and wrist fracture was reported due to motorcycle accident and determined not to be drug-related. In addition, no clinically significant changes from baseline were observed for ECGs, vital signs, physical examinations and laboratory assessments in either active or placebo groups. A few participants had ADAs present both before and after SM17 administration, and no trend in positive ADA was detected with ascending doses of SM17.

Concentration-time profiles from single IV administration of SM17 visually appeared to increase in a dose-dependent manner, however statistical analysis revealed mean AUCs increased in a more than dose-proportional fashion from 2 mg to 1200 mg. On the other hand, total exposure increased dose proportionally from 200 mg to 600 mg over three Q2W administrations. In addition, following multiple ascending doses, moderate accumulation was observed and steady state was not achieved by Day 29. The mean t_½ of SM17 after 200 – 600 mg multiple doses was approximately 14.6 to 18.5 days. This range is similar to current alarmin inhibitors in development for asthma and AD, such as CNTO 7160, an anti-IL-33 receptor monoclonal antibody (28).

As reported previously, part of the anti-inflammatory effect of attenuating alarmin signaling is a reduction in eosinophils (29–33). Therefore, in the present Phase I trial, eosinophil count was assessed as a putative proof-of-mechanism, however cell levels minimally changed after SM17 administration. This is probably because of the limitation of this study, in which only healthy volunteers were recruited and their basal eosinophil count were already within normal range (0 – 0.5x10⁹/L). In addition, steady-state levels were not obtained after three doses of SM17, which may also contribute to the lack of effect on eosinophils. Even though SM17 administration may not have a significant impact on healthy volunteers, our pre-clinical data suggested that it may possess a more pronounced inhibitory effect on eosinophils in asthmatic subjects. In the physiologically relevant model of allergic asthma, 5 mg/kg dose of SM17 markedly decreased the levels of Th2 cytokines and the number of ILC2 cells in BALF. Additionally, it effectively reduced goblet cell hyperplasia in the bronchial epithelium and the infiltration of mast cells and eosinophils into the lungs, demonstrating strong anti-asthmatic effects in the animals.

Potency of SM17 on suppressing Th2 responses in this asthma model aligns with our previously published findings in a 2,4-dinitrofluorobenzene (DNFB)-induced contact dermatitis model (25). In that study, SM17 also successfully reduced Th2 cytokine levels and epidermal thickness, as well as the infiltrations of mast cells, Th2 cells and eosinophils into the dorsal skin and ear tissues (25). Both models showed SM17 could effectively target multiple disease factors, indicating its potential as a powerful therapeutic option for treating Th2-associated diseases (34).

Many of the approved biologics for severe AD and asthma target ‘downstream’ cytokines in the Th2 inflammation cascade (35–37). For example, dupilumab is a humanized monoclonal antibody targeting alpha chain of IL-4/IL-13 receptor and has been approved for the treatments of both severe AD and asthma (38, 39). IL-5/IL-5R targeting antibodies, including mepolizumab, reslizumab and benralizumab, were also approved for severe eosinophilic asthma unresponsive to other therapies (40, 41). In asthma patients, these ‘downstream’ biologics can only reduce asthma annual exacerbation rates by approximately 50% (40, 42, 43). Therefore, there is still an unmet need for alternative therapies, particularly for patients who do not respond to conventional treatments (44, 45). To that end, therapies targeting ‘upstream’ mediators of the Th2 inflammatory cascade are required to be developed (46, 47). Alarmins such as IL-25, IL-33 and TSLP function at the initial stages of the allergy cascade and are anticipated to have a more comprehensive impact on airway inflammation, potentially offer more effective asthma management than currently therapies (30, 48). Indeed, tezepelumab, a fully humanized IgG2λ monoclonal antibody that specifically inhibits TSLP, was reported to reduce asthmatic exacerbations by 62%-71% (49). It is approved in the US for the add-on maintenance treatment of adult and pediatric patients aged 12 years and older with severe asthma (30). Anti-IL-33/anti-ST2 (IL-33 receptor) monoclonal antibodies also showed promising results in clinical trials (29, 50, 51), illustrating the potential of anti-alarmin therapies for Th2-regulated diseases. Inhibition of the IL-25 pathway is also predicted to have similar clinical outcomes in asthma patients.

Based on our pre-clinical studies and several research findings, a graphical illustration was created to explain the plausible mechanisms of SM17 in asthma ( Figure 7 ). In brief, when allergens like HDM encounter the airway epithelium, epithelial cells will release IL-25 into peripheral spaces and activate Th2 and ILC2 cells (32, 52). These target cells are responsible for secreting Th2 cytokines (‘downstream’ factors), including IL-4, IL-5, IL-9 and IL-13 (53). Each cytokine has its crucial role in the asthma pathogenesis. IL-4 is known to activate B cell and induce the IgE class-switching process (54, 55). IL-5 plays a critical role in maturation, activation and migration of eosinophils to the airways, which is also a major stimulator of eosinophilia in other Th2-driven diseases (56, 57). IL-9 mainly promotes mast cell proliferation and migration, resulting in mast cell infiltration in allergic airways (58, 59). IL-13 contributes to goblet cell hyperplasia and mucus secretion during airway inflammation, which eventually increases airway resistance and lead to asthma exacerbations (60, 61). As mentioned, IL-25 serves as ‘upstream’ cytokine and contributes to all four Th2 cytokine productions. Blocking of its receptor IL-17RB with SM17 may just offer inhibitory effects on these disease-contributing cytokines all at once (62), which could result in better restoration in normal lung histology and reduction in asthma exacerbations.

Comparing with other IV administrated monoclonal antibody therapies, one advantage SM17 holds is a fixed dose approach to drug administration. While IV treatments such as reslizumab apply weight-based dosing (mg/kg), SM17 was administered as a fixed dose (mg) in this study. As monoclonal antibodies tend to possess a wide therapeutic window, Hendrikx et al. advocate for fixed-dosing schedules since body weight has minor effects on IgG distribution and elimination (63). The authors also suggest that cost effectiveness can be gained in the preparation and administration of fixed-dose compared to body-size based dose therapies.

While the present study provides a relative comprehensive characterization of safety and PK profile for SM17 in healthy subjects, there are some limitations to be addressed, for instance, the safety and PK profile had not been explored in patients with asthma. In addition, the efficacy of SM17 in humans remains to be investigated in future clinical studies.

The ‘upstream’ role of alarmins in Th2 inflammatory disease makes these cytokines and their receptors ideal targets for treating chronic conditions associated with eosinophilia and high Th2 cytokine levels, such as asthma. As IL-25 contributes to the pathology of asthma, blockade of its receptor by SM17 may serve as a promising approach to treat this disease. Overall, SM17 was well tolerated and the findings of this Phase I study support further drug development in patients.