Rethinking Monospecific Antibody Therapy in Chronic Rhinosinusitis with Nasal Polyps: Dual- and Multispecific Antibodies

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disorder in which type 2 inflammation predominates but varies in its local organization, clinical context, and downstream tissue effects. Biologics targeting interleukin-4 receptor alpha, immunoglobulin E, the interleukin-5/interleukin-5 receptor axis, and thymic stromal lymphopoietin have expanded treatment options for severe disease and can improve polyp burden, nasal obstruction, olfactory function, quality of life, and corticosteroid- or surgery-related outcomes. However, responses remain variable across patients and clinical domains, and incomplete control may reflect target mismatch, persistent parallel inflammatory pathways, comorbid airway disease, or established tissue remodeling rather than insufficient pathway coverage alone. In this review, we summarize the mechanisms and clinical evidence for current monospecific antibodies and examine biological contexts that may contribute to variable treatment responses, including local IgE activity, microbial and antigenic amplification, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD), comorbid asthma, and persistent epithelial remodeling. We then discuss biomarkers, multidimensional response assessment, and clinical positioning of biologic therapy before evaluating the rationale, boundaries, molecular design, and current pipeline of dual- and multispecific antibodies. Attention is given to whether broader pathway targeting can provide incremental benefit over optimized monospecific therapy, while maintaining acceptable long-term safety, treatment practicality, and economic value. The future role of multispecific biologics in CRSwNP will depend on rational target pairing, comparative clinical evidence, and improved identification of patients most likely to benefit.

Introduction

Chronic rhinosinusitis (CRS) is a heterogeneous, chronic inflammatory disorder affecting the nasal mucosa and paranasal sinuses. Clinically, it is defined by persistent symptoms lasting at least 12 weeks, including nasal obstruction, rhinorrhea, facial pressure or pain, and olfactory dysfunction [1]. Based on endoscopic or radiographic findings, CRS is commonly divided into CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP) [2]. CRSwNP is strongly associated with type 2 inflammation. While Type 2 inflammation has historically been more prevalent in Western CRSwNP cohorts—accounting for approximately 80% of cases—epidemiological shifts reveal a progressively rising prevalence of type 2-predominant disease within Asian populations as well [3]. Pathophysiologically, type 2 CRSwNP is characterized by epithelial activation and the subsequent release of upstream “alarmins,” particularly thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25), and IL-33. This initial signal triggers downstream amplification mediated by IL-4, IL-5, and IL-13, resulting in eosinophilic inflammation, local immunoglobulin E (IgE) production, mucus hypersecretion, tissue edema, and structural mucosal remodeling [4–6].

The standard of care encompasses intranasal corticosteroids, saline irrigation, short courses of systemic corticosteroids, and endoscopic sinus surgery (ESS). However, achieving long-term disease control remains challenging in patients presenting with severe eosinophilic or type 2-high CRSwNP [7]. Although ESS restores sinus ventilation and facilitates topical drug delivery, it does not address all of the underlying molecular drivers of inflammation; consequently, disease recurrence remains common. This risk is particularly pronounced in patients with comorbid asthma, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD), or marked tissue eosinophilia. Biologics are generally positioned as add-on treatment for patients whose disease remains uncontrolled despite appropriate standard medical therapy and, where indicated, surgical management.

These therapeutic limitations have driven the development of biologic therapies targeting specific inflammatory cascades in severe CRSwNP. Monospecific antibodies targeting the interleukin-4 receptor alpha (IL-4Rα) subunit, IgE, the interleukin-5/interleukin-5 receptor (IL-5/IL-5R) axis, and, more recently, TSLP have translated endotype-guided treatment into clinical practice. Nevertheless, clinical responses remain variable. A subset of patients experiences only partial improvement, relapses upon treatment discontinuation, or requires switching between different biologics. Importantly, these outcomes should not automatically be interpreted as evidence that broader pathway inhibition is required. Before treatment escalation, the underlying disease biology, the appropriateness of the initial biologic selection, and the adequacy of standard medical and surgical management should be reassessed. In appropriately evaluated patients, however, persistent disease activity may reflect overlapping or compensatory inflammatory pathways that are not adequately controlled by a single-target antibody. Concurrently, clinical guidelines for biologic initiation in CRSwNP are evolving, reflecting a paradigm shift toward more practical, stratified treatment positioning in severe disease. Within this context, dual- and multispecific antibodies are being investigated as potential therapeutic strategies for carefully selected patients with residual disease activity. In this review, we summarize the mechanisms and clinical evidence for current monospecific biologics, examine the biological contexts underlying variable treatment responses and the evolving role of biomarkers in precision treatment, and critically evaluate the rationale and boundaries of broader pathway targeting. We further review the molecular design and clinical development of emerging dual- and multispecific antibodies and discuss the key challenges that will determine their future role in CRSwNP.

Current Monospecific Antibodies: Mechanisms and Clinical Evidence

Current biologics for CRSwNP target IL-4Rα, the IL-5/IL-5R axis, IgE, or TSLP. Because these pathways are interconnected, clinical response or target-associated biomarker changes should not be interpreted as evidence that the targeted molecule or cell population is the sole driver of disease. This section summarizes the principal mechanisms and clinical evidence for currently available monospecific antibodies.

Targeting the IL-4/IL-13 Axis

IL-4 and IL-13 are central mediators of type 2 inflammation in CRSwNP, exerting overlapping yet functionally distinct effects on the sinonasal mucosa. Both cytokines signal through receptor complexes containing the IL-4Rα subunit. The type I receptor complex (IL-4Rα/γc) primarily mediates IL-4 signaling in immune cells, whereas the type II receptor complex (IL-4Rα/IL-13Rα1), which responds to both IL-4 and IL-13, is predominantly associated with epithelial activation and tissue remodeling [8, 9]. Downstream signaling through Janus kinase (JAK)/signal transducer and activator of transcription 6 (STAT6), together with phosphoinositide 3-kinase and extracellular signal-regulated kinase pathways, promotes T helper 2 (Th2) polarization, IgE class switching, eosinophilic inflammation, mucus hypersecretion, epithelial barrier dysfunction, and subepithelial remodeling [10, 11].

Consistent with this broad biological role, IL-4Rα blockade has demonstrated the most comprehensive clinical benefit among current monospecific antibodies. Dupilumab, a fully human IgG4 monoclonal antibody targeting IL-4Rα, is approved for CRSwNP and remains the best-established agent in this class. In the phase 3 LIBERTY NP SINUS-24 and SINUS-52 trials, dupilumab improved Nasal Polyp Score (NPS), Nasal Congestion Score (NCS), Lund–Mackay computed tomography (CT) score, 22-item Sino-Nasal Outcome Test (SNOT-22) scores, and olfactory outcomes, while reducing the need for rescue systemic corticosteroids and surgery [12]. Stapokibart (CM310), another anti-IL-4Rα monoclonal antibody, has demonstrated efficacy in severe uncontrolled CRSwNP in phase 2 and phase 3 studies and has been approved in China for poorly controlled disease. In the CROWNS-2 trial, stapokibart reduced nasal polyp burden and improved NCS at 24 weeks, with additional benefits in CT scores, olfactory function, and health-related quality of life [13, 14].

The IL-4Rα/IL-13 therapeutic pipeline is expanding further. As summarized in Table 1, anti-IL-4Rα candidates under clinical development for CRSwNP include SSGJ-611, TQH2722, and QX005N, while the anti-IL-13 monoclonal antibody lebrikizumab is being evaluated in a phase 3 CRSwNP trial. Collectively, these therapeutic agents reinforce the clinical relevance of the IL-4/IL-13/IL-4Rα signaling axis in disease pathophysiology.

Table 1.

Current IL-4Rα- and IL-13-targeted therapeutic pipeline in CRSwNP

Target	Agent	Company	Stage in CRSwNP	Study ID
IL-4Rα	SSGJ-611	Sunshine Guojian Pharmaceutical	Phase 3	NCT06639295
IL-4Rα	TQH2722	Chia Tai Tianqing / Nanjing Shunxin / related developers	Phase 2	NCT06439381
IL-4Rα	QX005N	Qyuns / Huadong Medicine-linked development	Phase 2	ChiCTR20223317
IL-13	Lebrikizumab	Eli Lilly	Phase 3	NCT06338995

Despite its broad efficacy, IL-4Rα blockade does not achieve complete control across all clinical domains in every patient. Real-world studies have identified residual disease activity in a subgroup of patients, and olfactory improvement does not always parallel the reduction in nasal polyp size [15, 16]. Transient peripheral blood eosinophilia may also occur after dupilumab initiation, probably reflecting altered eosinophil trafficking after inhibition of IL-4/IL-13-dependent tissue-homing signals [17, 18]. However, peripheral eosinophilia alone does not establish persistent eosinophilic inflammation within sinonasal tissue or justify additional IL-5-directed treatment.

Targeting the IL-5/IL-5R Axis

The IL-5/IL-5R axis regulates eosinophil differentiation, activation, and survival, providing a strong biological rationale for targeting this pathway in eosinophilic CRSwNP. IL-5 signals through a type I cytokine receptor composed of IL-5Rα (CD125) and a common β-chain (CD131). Ligand binding induces receptor heterodimerization and activates the JAK/STAT and Ras/mitogen-activated protein kinase (MAPK) pathways [19]. Activated eosinophils release granule proteins and lipid mediators that contribute to epithelial injury, inflammatory amplification, and tissue remodeling [20–23].

Mepolizumab reduced nasal polyp burden and the need for surgery in the phase 3 SYNAPSE trial, with the MERIT trial extending these findings to East Asian populations [24, 25]. The long-acting anti-IL-5 antibody depemokimab also met its coprimary endpoints in the phase 3 ANCHOR-1 and ANCHOR-2 trials [26, 27]. Benralizumab, an afucosylated anti-IL-5Rα antibody that induces near-complete eosinophil depletion, improved NPS and nasal blockage in the OSTRO trial; however, several secondary outcomes, including SNOT-22 and time to surgery or systemic corticosteroid use, were not significantly improved [28, 29].

The relationship between eosinophil depletion and clinical benefit is not linear. Dexpramipexole produced profound reductions in blood and nasal polyp tissue eosinophils without reducing polyp size or improving symptoms, whereas mepolizumab achieved clinical benefit despite less complete eosinophil depletion [30]. These findings indicate that eosinophils are important components of type 2 CRSwNP but are unlikely to be the sole determinants of established polyp disease. Eosinophil heterogeneity and potential IL-5Rα-mediated effects on local IgE- and IgG4-expressing antibody-secreting cells may also contribute to this complexity, particularly in N-ERD [31, 32]. Experimental evidence further suggests that tissue-resident eosinophils may have homeostatic or regulatory functions distinct from those of inflammatory eosinophils. If analogous populations coexist in human nasal polyps, the extent of eosinophil depletion alone may not predict clinical benefit, and selective modulation of pathogenic eosinophil states may be more relevant than indiscriminate depletion.

Targeting the IgE Pathway

Beyond the actions of type 2 cytokines, IgE functions as an important amplifier of local inflammation in CRSwNP. Within nasal polyp tissue, B cells can undergo local class-switch recombination and receptor revision, followed by differentiation into IgE-producing plasma cells [33]. The resulting local IgE response is frequently polyclonal and may be present independently of systemic atopic status or serum allergen-specific IgE. By cross-linking FcεRI on mast cells and basophils, local IgE promotes the release of lipid mediators and inflammatory cytokines, thereby linking mucosal humoral immunity with type 2 effector responses.

Omalizumab binds free IgE, prevents its interaction with FcεRI, and downregulates FcεRI expression on effector cells. In the phase 3 POLYP 1 and POLYP 2 trials, omalizumab improved nasal polyp size, congestion, olfaction, SNOT-22 scores, and rhinorrhea [34]. Importantly, earlier randomized evidence demonstrated clinical benefit in patients with nasal polyps and asthma irrespective of conventional allergic status [35]. These findings suggest that systemic aeroallergen sensitization is not required for anti-IgE treatment to exert clinical activity in CRSwNP. The biological effects of anti-IgE therapy also extend beyond changes in circulating IgE alone. Clinical benefit with omalizumab has been observed across baseline blood eosinophil and serum IgE strata, supporting the view that neither marker alone adequately defines treatment responsiveness. In AERD, omalizumab has additionally been associated with reductions in peripheral blood eosinophils and downstream type 2 effector markers, including ECP and periostin, further illustrating the interconnected consequences of IgE blockade within the type 2 inflammatory network [36].

Despite these benefits, anti-IgE therapy has limitations. Open-label extension data showed recurrence of polyp burden and symptoms within 24 weeks of omalizumab discontinuation, suggesting that continuous treatment is typically required to maintain disease control [37]. In the phase 4 EVEREST trial of patients with CRSwNP and comorbid asthma, dupilumab outperformed omalizumab across major upper- and lower-airway endpoints [38]. However, the comparative superiority of IL-4Rα blockade in this population should not be interpreted as evidence that IgE is biologically unimportant or that omalizumab efficacy is determined solely by baseline serum IgE.

Targeting TSLP: Rationale, Current Evidence, and Emerging Therapeutic Potential in CRSwNP

TSLP is an epithelial-derived alarmin positioned upstream in the type 2 inflammatory cascade and represents an attractive therapeutic target in CRSwNP. It is produced primarily by epithelial cells in response to allergens, microbial stimuli, barrier injury, and environmental insults. TSLP signals through a heterodimeric receptor complex composed of TSLPR and IL-7Rα, activating downstream JAK/STAT pathways [39, 40]. Unlike downstream mediators, such as IL-5 or IgE, TSLP influences multiple type 2 pathways simultaneously. Through its effects on dendritic cells, CD4 + T cells, group 2 innate lymphoid cells, eosinophils, basophils, and mast cells, TSLP amplifies IL-4-, IL-5-, and IL-13-driven inflammation and contributes to mucus hypersecretion, airway hyperreactivity, and tissue remodeling [41, 42].

Tezepelumab, a fully human monoclonal antibody that binds TSLP and prevents its interaction with the TSLPR/IL-7Rα receptor complex, is now approved in the United States as add-on maintenance treatment for inadequately controlled CRSwNP in patients aged 12 years and older. Clinical development in CRSwNP is currently led by tezepelumab, a fully human monoclonal antibody that binds TSLP and prevents its interaction with the TSLPR/IL-7Rα receptor complex. In the phase 3 WAYPOINT trial, 408 adults with severe uncontrolled CRSwNP received tezepelumab or placebo in addition to standard care for 52 weeks [43]. Tezepelumab significantly improved total NPS, NCS, olfactory outcomes, SNOT-22, and radiological disease burden. It also markedly reduced the requirement for nasal polyp surgery and systemic corticosteroids [44].

The broader TSLP/TSLPR-targeted pipeline is also expanding. As shown in Table 2, CM326 has also generated peer-reviewed CRSwNP-specific evidence. In the phase 1b/2a DUBHE trial, CM326 administered every 2 weeks improved NPS at week 16 in patients with eosinophilic CRSwNP and was associated with reductions in peripheral blood and tissue eosinophils and circulating IL-5 and IL-13 [45]. In addition, Verekitug, which targets TSLPR, has completed phase 2 evaluation in the VIBRANT study. However, detailed CRSwNP-specific efficacy and safety results have not yet been published in a peer-reviewed article, and its clinical positioning therefore remains uncertain. Bosakitug and GSK5784283 are also in phase 2 development, although peer-reviewed CRSwNP-specific data remain limited [46]. As with other monospecific approaches, TSLP blockade may still be constrained by parallel alarmin signaling and the incomplete reversibility of established tissue remodeling. Clinical benefit from TSLP blockade should not be interpreted as proof that TSLP is the sole upstream driver of CRSwNP or that the therapeutic mechanism has been fully defined, because parallel epithelial alarmins, downstream pathway redundancy, and established tissue remodeling may remain active.

Table 2.

Current TSLP- and TSLPR-directed therapeutic pipeline in CRSwNP

Target	Agent	Company	Stage in CRSwNP	Study ID
TSLP	Tezepelumab	AstraZeneca / Amgen	Marketed	WAYPOINT
TSLP	Bosakitug	Biosion / Chiatai Tianqing / Aclaris Therapeutics	Phase 3	NCT07107256
TSLP	GSK5784283(formerly SHR-1905/AIO-001)	GSK / Aiolos Bio	Phase 2	NCT05891483
TSLP	CM326	Keymed Biosciences / CSPC / JMT-BiO	Phase 2	NCT06372678
TSLPR	Verekitug	Astellas / Upstream Bio	Phase 2	VIBRANT

Biological Contexts Underlying Variable Responses to Biologic Therapy

The clinical heterogeneity of CRSwNP extends beyond differences in the abundance of individual type 2 cytokines. Patients with a similar polyp phenotype may differ in the organization of local mucosal immunity, environmental and microbial exposures, comorbid airway disease, and the extent of established tissue remodeling. Although validated predictors of differential biologic response remain limited, these biological contexts may modify the relative contribution of IL-4/IL-13, IL-5, IgE, epithelial alarmins, and effector-cell pathways and may therefore contribute to variable and domain-specific responses to biologic therapy [47].

Local Versus Systemic Immune Activity and Antigenic Amplification

Serum and tissue immune signals are not interchangeable in CRSwNP [48]. Nasal polyp tissue supports local class-switch recombination, receptor revision, and IgE production, and this local IgE response may not parallel serum total IgE or conventional systemic atopic status [33]. This distinction is consistent with the clinical efficacy of omalizumab in both allergic and nonallergic patients with nasal polyps and asthma [35]. Evidence from non-atopic asthma further shows that omalizumab can reduce bronchial mucosal IgE and improve lung function despite the absence of conventional systemic atopy, supporting the concept that local tissue IgE activity may remain biologically relevant when systemic allergic sensitization is absent [49]. Aeroallergen sensitization may contribute to coexisting allergic rhinitis and the overall burden of upper-airway symptoms, but it does not by itself account for local IgE activity or the persistence of nasal polyps [50]. Systemic atopy, circulating IgE, and local mucosal IgE should therefore be regarded as related but biologically non-equivalent features.

Local inflammatory activity may also be amplified by microbial factors in selected patients [51, 52]. Staphylococcus aureus is of particular interest because biofilm-associated products may impair epithelial function, whereas staphylococcal enterotoxins can promote broad immune activation and local enterotoxin-specific antibody responses [53]. However, the detection of S. aureus alone does not define a pathogenic microbial endotype, as colonization may also occur in individuals without CRS and its biological effects appear to depend on biofilm activity, virulence factors, and host susceptibility [54].

Fungal antigens represent another potential source of local immune activation, but fungal detection or sensitization should not be equated with allergic fungal rhinosinusitis (AFRS). AFRS is a distinct clinicopathological entity characterized by fungal hypersensitivity, eosinophilic mucin containing noninvasive fungal elements, nasal polyposis, and characteristic radiological abnormalities [55]. Although prominent type 2 inflammation is common in AFRS, evidence supporting biologic therapy remains limited, and findings from general CRSwNP trials cannot yet be directly extrapolated to this population. Whether sustained co-inhibition of multiple type 2 pathways alters antifungal host defense, fungal clearance, or recurrence risk in AFRS is unknown and requires dedicated safety and efficacy studies.

Distinct Inflammatory Contexts: N-ERD and Comorbid Asthma

N-ERD represents a distinct clinical and inflammatory syndrome characterized by CRSwNP, asthma, and respiratory reactions to cyclooxygenase-1-inhibiting NSAIDs [56]. Its pathophysiology involves not only eosinophilic and type 2 inflammation but also dysregulated arachidonic acid metabolism, reduced protective prostaglandin E₂ signaling, excessive cysteinyl leukotriene and prostaglandin D₂ production, and activation of mast cells and platelets. These interacting pathways illustrate why the inflammatory activity of N-ERD cannot be adequately represented by blood eosinophils or a single type 2 cytokine [32].

Comorbid asthma provides another example of biological heterogeneity within type 2 airway disease. Although the upper and lower airways share several inflammatory pathways, the relative contributions of epithelial alarmins, IgE, eosinophils, mucus-producing cells, and structural remodeling may differ between the sinonasal and bronchial compartments [57]. Consequently, therapeutic responses in the two compartments may not be concordant, and evidence derived from severe asthma cohorts with comorbid CRSwNP should be distinguished from that generated in CRSwNP-specific trials. Improvement in lower-airway disease therefore does not necessarily imply equivalent control of nasal polyps, olfactory dysfunction, or sinonasal quality of life [58]. In this review, comorbid asthma is considered primarily as a modifier of CRSwNP biology, outcome assessment, and biologic selection. Evidence from patients whose asthma independently meets criteria for biologic therapy should be distinguished from evidence in patients receiving a biologic principally for uncontrolled CRSwNP.

Symptom-Domain Heterogeneity and Persistent Tissue Remodeling

Heterogeneity is also evident across sinonasal clinical outcomes. Nasal polyp size, nasal obstruction, mucus production, olfactory dysfunction, and health-related quality of life are related but non-equivalent disease domains, and improvement in one outcome does not necessarily predict a comparable response in another. In particular, recovery of olfactory function may not parallel the reduction in nasal polyp size.

Persistent disease may also reflect tissue changes that are only partly dependent on ongoing cytokine activity. Chronic inflammation can produce epithelial barrier dysfunction, extracellular matrix remodeling, and persistent alterations in epithelial progenitor cells that may not be immediately reversed by cytokine blockade [59]. Respiratory epithelial progenitor cells can retain an intrinsic memory of previous IL-4/IL-13 exposure, providing a potential mechanism for sustained or recurrent tissue dysfunction even after inflammatory activity has been reduced [60].

Together, these observations suggest that variable biologic responses in CRSwNP may reflect differences not only in the intensity of type 2 inflammation, but also in its local organization, clinical context, and the extent to which persistent symptoms are driven by reversible inflammation versus established tissue change.

Biomarkers and Precision Medicine in CRSwNP

Biologic therapy has introduced endotype-informed treatment into CRSwNP; however, precision medicine remains constrained by the absence of validated biomarkers that can reliably distinguish among available biologics or predict response across individual clinical domains. Current treatment selection therefore relies on an integrated assessment of clinical phenotype, comorbid airway disease, previous surgery, corticosteroid burden, and available blood or tissue biomarkers [61, 62]. As the number of biologic options increases, this limitation becomes increasingly relevant.

Biomarkers for Biologic Selection

Among routinely available biomarkers, blood eosinophils, total serum IgE, and FeNO are the most practical; however, none is sufficient on its own to guide biologic selection. Blood eosinophils are widely used to characterize type 2 inflammation, and higher baseline levels may enrich for a greater probability of response to some biologics; however, clinically meaningful benefit has been observed across eosinophil strata [63]. This supports their use as a probability-enriching marker rather than a strict treatment threshold. Total serum IgE remains necessary for omalizumab dosing but does not reliably reflect local mucosal IgE activity and is not a consistent predictor across biologic classes [64]. FeNO may reflect IL-4/IL-13-driven airway inflammation, particularly in patients with comorbid asthma, but its utility in CRSwNP remains supportive rather than decisive [63, 65, 66].

Tissue-based biomarkers may provide more direct information about sinonasal inflammation. Higher baseline IgE-positive cell counts in nasal polyp tissue have been associated with omalizumab response, while tissue eosinophilia and eosinophil cationic protein reflect local eosinophilic activity and have been associated with disease severity or postoperative recurrence. Other candidates, including periostin and OPG, remain investigational and are not sufficiently validated for routine treatment selection [67–69].

Treatment Goals and Multidimensional Response Assessment

Treatment response in CRSwNP should be assessed across multiple, non-equivalent clinical domains. Relevant outcomes include nasal polyp size, nasal obstruction, mucus or rhinorrhea burden, olfactory function, health-related quality of life, systemic corticosteroid exposure, the need for surgery, and control of comorbid asthma. The relative importance of these outcomes varies among patients; for example, recovery of smell may represent the principal treatment priority for one patient, whereas another may prioritize relief of obstruction, reduction in mucus symptoms, or avoidance of further surgery.

These domains may respond discordantly and should not be collapsed into a single definition of biologic success. A reduction in NPS does not necessarily parallel recovery of olfaction, improvement in SNOT-22, or control of lower-airway disease. Response assessment should therefore distinguish between complete response, clinically meaningful but domain-limited improvement, and persistent uncontrolled disease [16].

Interpretation across biologic trials is limited by substantial heterogeneity in patient selection, disease-subgroup composition, treatment duration, outcome measures, and data reporting. In particular, inconsistent representation of patients with comorbid asthma, N-ERD, or previous sinus surgery, together with variable assessment time points and reporting formats, complicates indirect comparisons between biologics and may obscure differential treatment effects across clinically relevant subgroups. Greater standardization of trial design, outcome reporting, and subgroup characterization is therefore needed to support meaningful comparative effectiveness analyses and clinical treatment selection [70].

Treatment Positioning: Initiation, Continuation, and Switching

Recent guideline documents suggest that biologic use in CRSwNP is becoming more structured and clinically practical [71]. The EPOS/EUFOREA 2023 update continues to position biologics primarily for severe, uncontrolled CRSwNP after appropriate medical therapy and, in most cases, prior surgery, using a multidimensional assessment incorporating type 2 inflammation, corticosteroid need, quality-of-life impairment, olfactory dysfunction, and comorbid asthma. More recent Chinese recommendations place greater emphasis on objective initiation criteria related to polyp burden, symptom severity, and type 2 inflammatory status, indicating a shift toward more operational treatment frameworks [72, 73].

Continuation or switching of biologic therapy should similarly be based on an adequate treatment trial and multidimensional reassessment. Persistent disease activity should prompt evaluation of treatment duration and adherence, adequacy of topical medical therapy and previous surgery, the clinical domain that remains uncontrolled, comorbid lower-airway disease, and the possibility of an alternative inflammatory driver or a predominantly structural contributor. Switching to another monospecific biologic may be appropriate in patients with inadequate overall response, unacceptable adverse effects, persistent corticosteroid dependence, or discordant upper- and lower-airway control despite an adequate treatment period [71, 74].

Importantly, no biomarker or clinical profile has yet been validated to identify patients who specifically require dual- or multispecific pathway inhibition. N-ERD, comorbid asthma, marked eosinophilic inflammation, and severe postoperative recurrence identify patients with greater disease burden or more complex inflammatory backgrounds, but they should not be regarded as direct selection criteria for broader pathway blockade. Distinguishing inadequate target selection, domain-specific response, persistent structural disease, and residual inflammatory activity is therefore essential before considering more extensive pathway-targeted strategies.

Rationale and Boundaries of Dual- and Multispecific Targeting in CRSwNP

Biological Rationale for Coordinated Pathway Targeting

CRSwNP is not a single-cytokine disease but a layered inflammatory network in which IL-4/IL-13, IL-5, IgE, and epithelial alarmins such as TSLP, IL-33, and IL-25 interact through overlapping and partially redundant pathways [5, 6]. Blocking one component of this network may substantially reduce disease activity while leaving other biologically active pathways intact [47]. IL-5/IL-5R blockade, for example, primarily suppresses eosinophil-associated inflammation but does not directly inhibit IL-4/IL-13-mediated epithelial dysfunction, mucus production, or local IgE responses. Conversely, anti-IgE therapy reduces IgE-dependent mast-cell and basophil activation without directly suppressing epithelial alarmin signaling [22, 75]. The major components of this interconnected inflammatory network and the mechanisms that may limit the efficacy of single-target biologics are summarized in Fig. 1.

Fig. 1.

Mechanistic basis of type 2 inflammation and the limitations of single-target biologics in CRSwNP

The broader clinical effects of IL-4Rα blockade provide an instructive example of how intervention at an interconnected node can influence multiple downstream components of type 2 inflammation. IL-4Rα inhibition reduces signaling by both IL-4 and IL-13 and consequently affects biomarkers related to epithelial activation, eosinophil recruitment, and IgE production. Indirect comparisons and network meta-analyses have generally found IL-4Rα-directed therapy to provide broad and consistent benefits across several CRSwNP outcomes [76, 77]. However, these comparisons do not establish that broader molecular coverage itself is responsible for superior efficacy, because differences in trial populations, study design, and outcome reporting limit mechanistic inference from cross-trial comparisons [70].

This network architecture nevertheless provides a biological rationale for investigating combinations of complementary targets. Potential strategies include pairing an upstream epithelial signal with a downstream effector pathway, co-targeting two effector pathways that remain simultaneously active, or, more selectively, integrating additional inflammatory nodes within a multispecific construct [78]. The biological justification for such combinations should therefore depend on functional complementarity between the targets rather than simply on increasing the number of inhibited cytokines.

Clinical Positioning of Broader Pathway Targeting

The biological rationale for broader pathway inhibition does not automatically translate into a clinical indication for dual- or multispecific treatment. An incomplete response to a monospecific biologic may reflect insufficient treatment duration, inadequate background therapy, an inadequately matched biologic target, discordant upper- and lower-airway disease, or persistent structural abnormalities rather than insufficient pathway coverage alone [71, 79]. Persistent symptoms should therefore prompt reassessment of the clinical domain that remains uncontrolled, the adequacy of standard medical and surgical care, and potentially modifiable causes of treatment failure before broader pathway inhibition is considered. Importantly, prior sinus surgery should not be regarded simply as a binary variable. The extent and completeness of ESS may influence subsequent medical treatment, including biologic effectiveness. Recent expert consensus emphasizes that adequate surgery should clear nasal polyps and diseased mucosa while creating favorable conditions for topical therapy and supports complete sinus surgery before monoclonal antibody therapy when clinically appropriate. Observational evidence further suggests that more extensive surgery before dupilumab treatment may be associated with greater improvements in NPS and subjective outcomes [36, 80].

Switching between monospecific biologics is already used in clinical practice when the initial agent provides inadequate disease control or causes unacceptable adverse effects [79, 81]. In a multicenter Canadian cohort, 16% of patients switched biologics, most commonly from mepolizumab to dupilumab, with inadequate efficacy being a major reason for treatment change. The observation that some patients improve after switching to another monospecific target is consistent with the possibility that an inadequate response may sometimes reflect target mismatch rather than an inherent requirement for simultaneous multi-pathway inhibition.

At present, validated biomarkers capable of identifying patients who specifically require dual- or multispecific pathway inhibition are not available [61, 78]. Dual- or multispecific antibodies may ultimately be most relevant to patients who remain clinically uncontrolled after appropriate reassessment and in whom complementary inflammatory pathways remain biologically active. Demonstrating such a clinical niche will require evidence that broader pathway coverage provides an incremental advantage over optimized monospecific treatment.

Multispecific Antibodies Versus Combination Biologic Therapy

Simultaneous pathway inhibition can theoretically be achieved either by administering separate biologics or by incorporating multiple binding specificities into a single molecular construct [82]. Combination biologic therapy offers greater flexibility because individual agents can, in principle, be selected, adjusted, or discontinued independently; however, experience with simultaneous use of two biologics in CRSwNP remains limited, and established guidance for this strategy is lacking. The use of two separate biologics may also introduce additional treatment burden, cost, and pharmacokinetic complexity, particularly when long-term therapy is required.

A multispecific antibody, by contrast, integrates two or more binding specificities within a single molecular construct, allowing coordinated systemic exposure while making valency, avidity, pharmacokinetics, and relative target engagement dependent on the molecular architecture [83]. This coordinated design may simplify dosing and exposure, but it also reduces therapeutic flexibility because the relative activity against each target is predetermined by the molecular construct rather than adjusted independently in clinical practice [82]. A multispecific molecule should therefore not be regarded simply as the pharmacological equivalent of administering two established monoclonal antibodies together. Its dose-response relationship, tissue distribution, target engagement, and safety profile require independent clinical evaluation.

What Evidence is Needed to Establish Clinical Value?

The central clinical question is not whether dual- or multispecific antibodies can inhibit more pathways, but whether broader molecular coverage produces a clinically meaningful incremental benefit over the best available monospecific therapy. Future trials should therefore evaluate patient-relevant outcomes, including nasal obstruction, mucus or rhinorrhea burden, olfactory function, health-related quality of life, systemic corticosteroid exposure, and the need for further surgery. Where feasible, active comparator trials against an established monospecific biologic would provide more clinically informative evidence than placebo-controlled efficacy alone. Trial design should also incorporate standardized outcome definitions, assessment time points, and data-reporting formats to permit meaningful comparisons across therapeutic classes.

Prespecified analyses according to clinically and biologically relevant subgroups will be important for determining whether particular patient populations derive disproportionate benefit from broader pathway inhibition. These analyses should distinguish patients with N-ERD, comorbid asthma, marked eosinophilic inflammation, previous sinus surgery, and other features associated with more complex or recurrent disease, while avoiding the assumption that any of these characteristics alone predicts benefit from multispecific therapy.

Any incremental efficacy must also be weighed against the safety consequences of sustained co-inhibition of multiple immune pathways [78]. Long-term evaluation should therefore address infection risk, immunogenicity, treatment-related adverse events, and the consequences of sustained modulation of pathways that also participate in normal immune and tissue homeostasis. The clinical value of dual- and multispecific antibodies will ultimately depend on incremental efficacy, appropriate patient selection, and acceptable long-term safety rather than on the number of molecular targets incorporated into a single construct.

Dual- and Multispecific Antibodies

Design Logic, Molecular Format, and Pharmacological Properties of Dual- and Multispecific Antibodies

The development of dual- and multispecific antibodies in CRSwNP is guided by two interrelated considerations: rational target pairing and molecular format. The goal is not simply to add targets, but to combine biologically connected specificities within a single construct and match them to a structure that ensures appropriate valency, stability, tissue bioavailability, and pharmacokinetic behavior [74, 84].

Target combinations are typically selected to address a defined biological problem, such as co-blocking cooperating pathways, suppressing a dominant pathway alongside an escape mechanism, or integrating complementary immune functions into a single therapeutic molecule. These principles are well established in oncology, where bispecific and multispecific antibodies have been developed to redirect immune effector cells, co-modulate cooperating pathways, improve tissue or target selectivity, and overcome resistance mechanisms [85]. Amivantamab co-targets EGFR and MET to overcome signaling cooperation and resistance mechanisms, whereas mosunetuzumab links CD20 and CD3 to redirect T-cell cytotoxicity toward malignant B cells. More recently, PD-1/VEGF bispecific antibodies have demonstrated another strategy in which paired targets regulate distinct but complementary disease-sustaining processes [86–88].

Antibody development begins with selection of a disease-relevant target or target pair, followed by generation or screening of candidate antibodies using approaches such as immune-cell screening, phage or yeast display, and transgenic animal platforms. Candidates are then evaluated for target specificity and affinity before optimization of stability, Fc function, pharmacokinetics, tissue exposure, manufacturability, and immunogenicity. Candidates that are not fully human may additionally require humanization. For multispecific molecules, these steps are accompanied by optimization of chain pairing, binding-domain geometry, relative potency against each target, aggregation risk, and coordinated target engagement.

Molecular format is equally critical, as identical target pairs may exhibit different behavior depending on structural design. Current platforms include IgG-like bispecific antibodies, fragment-based constructs, dual-affinity retargeting molecules, tandem diabodies, and nanobody-based formats. Each platform involves trade-offs in stability, half-life, manufacturability, tissue distribution, and modularity. IgG-like formats are generally preferred when Fc-mediated stability and prolonged systemic exposure are required, whereas fragment-based and nanobody-derived formats may provide greater flexibility and tissue penetration, often at the cost of reduced half-life unless specifically engineered for extension [74]. Lunsekimig provides a practical example of how molecular architecture can be used to balance multispecificity and pharmacokinetics. Its pentavalent NANOBODY construct contains two TSLP-binding domains, two IL-13-binding domains, and an albumin-binding domain designed to extend systemic half-life through FcRn-mediated recycling [89].

These design considerations are directly relevant to CRSwNP. In a disease that often requires long-term maintenance therapy and is characterized by structurally remodeled sinonasal tissue, multispecific constructs must be optimized not only for broad pathway coverage but also for adequate tissue bioavailability, favorable Fc behavior, dosing convenience, and durability [90, 91]. The goal is therefore not merely to expand the biologic pipeline, but to develop molecules that more effectively address the overlapping inflammatory pathways and treatment-refractory disease biology of CRSwNP while avoiding the practical complexity of empirically combining multiple biologics [84].

From a pharmacological perspective, the molecular architecture of a dual- or multispecific antibody determines more than its binding spectrum. It also influences valency, avidity, serum persistence, receptor occupancy, tissue distribution, and manufacturability [83]. IgG-like formats retain an Fc region and therefore usually have greater molecular stability and longer systemic exposure through neonatal Fc receptor-mediated recycling. This property may be advantageous for chronic diseases such as CRSwNP, in which durable pathway suppression and convenient maintenance dosing are important. By contrast, fragment-based, scFv-based, or nanobody-derived formats are smaller and more modular, which may improve tissue access or allow flexible addition of binding domains, but these advantages are often counterbalanced by shorter plasma half-life unless half-life extension is engineered. Therefore, the same target combination may have different clinical implications depending on whether it is built as a full-length IgG-like molecule, an Fc-fusion construct, or a fragment-based multispecific antibody.

Current Pipeline and Target-Combination Strategies

As summarized in Table 3, the current bispecific and trispecific pipeline relevant to CRSwNP and related type 2 airway diseases can be categorized according to target-combination strategy and stage of development. The major target-combination strategies and their expected pharmacological advantages are illustrated in Fig. 2.

Table 3.

Current dual- and multispecific antibody pipeline relevant to CRSwNP and related type 2 airway disease

Target combination	Agent	Company	Stage	NCT number
TSLP + IL-13	Lunsekimig	Sanofi	Phase 2a in CRSwNP	NCT06454240
IL-4Rα + TSLP	IBI3002	Innovent Biologics (Suzhou) Co. Ltd	Phase 1 / early phase 1 in healthy participants and asthma	NCT06213844; NCT06947408
IL-4Rα + IL-5	BBT002	Bambusa Therapeutics	Phase 1/2 study in healthy volunteers and CRSwNP with comorbid asthma	NCT07436949
IL-4Rα + IL-5	RC1416	Nanjing RegeneCore Biotech Co., Ltd	Phase 1b in asthma / type 2 airway disease	NCT06911866
IL-4 + IL-13 + TSLP	PF-07275315 (tilrekimig)	Pfizer	Phase 2 in type 2 inflammatory disease	NCT07363694
IL-4 + IL-13 + IL-33	PF-07264660	Pfizer	Early clinical development in type 2 inflammatory disease	NCT05995964

Fig. 2.

Representative target-combination strategies for dual- and multispecific antibodies in CRSwNP and related type 2 airway diseases

Among the candidates currently in development, lunsekimig is the most directly relevant to CRSwNP. Its TSLP/IL-13 design links upstream epithelial alarmin activity with a major downstream type 2 effector pathway [89, 92]. The phase 2a DUET study (NCT06454240), a randomized, double-blind, placebo-controlled trial in adults with inadequately controlled CRSwNP, has now been completed [93]. Topline results announced in April 2026 showed that lunsekimig met the primary endpoint of change in NPS at Week 24 and the key secondary endpoints of nasal congestion/obstruction score and Lund–Mackay CT score. However, detailed CRSwNP-specific results have not yet been published in a peer-reviewed article, and the magnitude, subgroup distribution, and durability of benefit therefore remain to be fully evaluated. Conceptually, this approach reflects a shift from selecting a single dominant cytokine to pairing biologically connected pathways within a single therapeutic construct.

A second strategy is IL-4Rα/IL-5 co-targeting, represented by BBT002 and RC1416. This approach combines inhibition of the IL-4/IL-13 axis with direct suppression of IL-5-dependent eosinophilic inflammation, thereby targeting two major components of type 2 disease. Early data for BBT002 suggest stronger inhibition of IL-4-, IL-13-, and IL-5-driven TF-1 cell proliferation than single-target comparator antibodies, together with synergistic anti-inflammatory activity in a PPE-induced COPD mouse model [94]. BBT002 has subsequently been registered for a phase 1/2 study evaluating healthy volunteers and patients with CRSwNP and comorbid asthma (NCT07436949), with safety, pharmacokinetics, pharmacodynamics, immunogenicity, and exploratory clinical activity included among the study objectives. However, peer-reviewed CRSwNP-specific efficacy data for this target combination remain unavailable.

A third direction involves simultaneous suppression of three type 2 inflammatory pathways. PF-07275315 (tilrekimig), which targets IL-4, IL-13, and TSLP, and PF-07264660 (ompekimig), which targets IL-4, IL-13, and IL-33, illustrate efforts to determine whether three coordinated inflammatory nodes can be incorporated into a single molecule [95]. Trispecific antibodies also illustrate a distinct engineering concept. Instead of simply mixing three monoclonal antibodies, a trispecific molecule integrates three binding specificities into a single scaffold, allowing coordinated exposure, unified pharmacokinetics, and potentially synchronized blockade of related inflammatory pathways. In type 2 airway inflammation, this may be particularly relevant when upstream alarmin release and downstream cytokine signaling coexist in the same patient. However, greater molecular complexity also increases the importance of molecular design. The spatial arrangement of binding domains, binding valency for each target, Fc engineering, chain-pairing control, and developability properties such as stability, aggregation risk, viscosity, and immunogenicity may all influence whether a trispecific construct can be translated into a practical long-term therapy [91].

Overall, the pipeline suggests three major strategic directions for airway disease: combining an alarmin with a downstream effector pathway, pairing two type 2 effector axes, or extending toward simultaneous suppression of three inflammatory nodes. For CRSwNP, the key question will be which strategy proves most biologically coherent, clinically effective, and practical for long-term disease management.

Therapeutic Practicality and Translational Barriers

Beyond broader target coverage, dual- and multispecific antibodies may also improve the practical use of biologic therapy in chronic airway disease. Current biologics for CRSwNP are effective for many patients, but most require repeated long-term administration, creating burdens related to treatment frequency, adherence, and cost. Next generation multispecific constructs are therefore being developed not only to broaden pathway coverage but also to improve half-life, molecular stability, Fc behavior, and dosing convenience [82, 84]. Antibody format may further influence tissue access and distribution, with different architectures presenting distinct trade-offs between mucosal penetration and systemic persistence [96]. These considerations are particularly relevant in CRSwNP, where treatment is often prolonged and the target tissue is structurally remodeled.

Half-life extension is an important practical consideration in chronic inflammatory disease. Fc-containing IgG-like formats may support longer dosing intervals through FcRn-mediated recycling, whereas smaller fragment-based formats may require Fc fusion, albumin-binding domains, PEGylation, or other half-life-extension strategies. However, improved systemic exposure should not be equated with greater activity in nasal polyp tissue [97]. Edema, mucus hypersecretion, epithelial barrier dysfunction, and stromal remodeling may alter local distribution, retention, and target engagement [98, 99]. Future dual- and multispecific antibodies should therefore be evaluated using both systemic pharmacokinetics and evidence of durable pathway suppression within sinonasal tissue [100, 101].

Greater molecular complexity also introduces important developmental trade-offs. Broader target coverage may enhance inflammatory suppression, but it can complicate manufacturability, dose selection, immunogenicity assessment, and safety monitoring [82, 102]. These challenges are particularly relevant in CRSwNP, where treatment is intended to provide durable disease control in patients who often have a history of surgery, repeated oral corticosteroid exposure, and comorbid asthma or N-ERD [98, 103]. The central translational question is whether dual- and multispecific antibodies can provide broader inflammatory control while maintaining sufficient tissue-level activity, acceptable long-term safety, feasible dosing regimens, and a meaningful advantage over the best available monospecific biologics.

Challenges and Future Perspectives

Economic Sustainability and Value-Based use of Biologics

Cost remains a major barrier to the broader use of biologics and is likely to be equally relevant for future dual- and multispecific antibodies. In CRSwNP, biologics provide substantial clinical benefit; however, treatment is expensive and typically requires long-term maintenance rather than short-term intervention. Although these agents have improved the management of severe disease, access remains constrained by cost, reimbursement policies, and uncertainty regarding their long-term value relative to surgery or optimized standard care [104].

These concerns may become more pronounced as structurally complex multispecific agents enter development. In principle, a single multitarget molecule could improve treatment efficiency by reducing the need for sequential treatment changes and simplifying long-term administration. However, these potential advantages remain unproven and should not be assumed to lower overall treatment costs, because greater structural and manufacturing complexity may increase development and production costs. Future multispecific agents will therefore need to demonstrate not only clinical efficacy but also meaningful incremental value over optimized monospecific therapy, including durability of response, treatment burden, cost-effectiveness, and real-world utility. Their economic justification will ultimately depend on whether the additional clinical benefit is sufficient to offset the greater molecular and manufacturing complexity [105].

Long-Term Safety and Immune Homeostasis

Long-term safety is another critical consideration. Current evidence suggests that approved biologics for CRSwNP are generally well tolerated, and both real-world data and long-term analyses support an acceptable safety profile [106, 107]. However, most available evidence derives from monospecific biologics, and these safety assumptions cannot necessarily be extrapolated to agents that simultaneously suppress multiple inflammatory pathways.

This issue is particularly relevant in CRSwNP because the sinonasal mucosa is continuously exposed to inhaled antigens, microbes, and repeated local injury. Type 2 cytokines and epithelial alarmins participate not only in pathological inflammation but also in mucosal immune regulation and tissue homeostasis. More extensive pathway co-inhibition may therefore alter host-defense or repair responses in ways that cannot be predicted simply by combining the safety profiles of the corresponding monospecific agents.

Future studies should therefore evaluate not only short-term treatment-emergent adverse events but also respiratory infection risk, mucosal integrity, immunogenicity, durability of response, and the consequences of sustained pathway co-inhibition during long-term treatment. Particular attention will be required when increasingly broad combinations incorporate both upstream epithelial alarmins and downstream effector cytokines.

Perspectives and Future Directions

The next phase of biologic therapy in CRSwNP will depend on whether broader pathway inhibition can translate into a clinically meaningful advantage over established monospecific treatment. For dual- and multispecific antibodies, this will require evidence of incremental benefit in patient-relevant outcomes, durability of disease control, reductions in systemic corticosteroid use and the need for surger, and treatment practicality.

Equally important will be defining the patients in whom such additional pathway coverage is justified. Current inflammatory biomarkers remain insufficient to identify a population that specifically requires multispecific therapy, and future development should therefore incorporate prospective biomarker analyses and clinically relevant subgroup stratification rather than relying solely on overall treatment effects. Evidence generated in patients with N-ERD, comorbid asthma, recurrent disease after surgery, or other complex inflammatory phenotypes may be particularly informative, but these characteristics should not be assumed a priori to predict benefit from broader pathway inhibition.

Ultimately, the place of dual- and multispecific antibodies in CRSwNP will depend on comparative efficacy, long-term safety, molecular and treatment practicality, economic value, and the ability to define a population in which broader pathway coverage provides a meaningful advantage over optimized current care [72].

Conclusion

Biologic therapy has transformed the management of CRSwNP by making pathway-targeted treatment a realistic option for patients whose disease remains uncontrolled despite appropriate standard care. Monoclonal antibodies targeting IL-4Rα, IgE, IL-5/IL-5R, and TSLP have demonstrated substantial benefits across nasal polyp burden, symptoms, olfaction, health-related quality of life, and corticosteroid- or surgery-related outcomes. Nevertheless, variable and domain-specific responses, relapse after treatment discontinuation, and the need for biologic switching underscore the biological and clinical heterogeneity of CRSwNP and the limitations of interpreting the disease through a single inflammatory pathway.

Dual- and multispecific antibodies offer a mechanistically plausible strategy for coordinating the inhibition of complementary inflammatory pathways within a single therapeutic construct. Their potential value, however, should not be inferred from broader target coverage alone. Clinical adoption will require evidence that multispecific approaches provide meaningful incremental benefit over optimized monospecific therapy, together with acceptable long-term safety, practical molecular design, and economic value. Equally important will be the identification of patients in whom persistent disease reflects biologically relevant pathway overlap rather than inadequate treatment selection, insufficient standard care, or irreversible structural disease. The future role of dual- and multispecific antibodies in CRSwNP will therefore depend on the convergence of rational target pairing, comparative clinical evidence, biomarker-informed patient selection, and long-term translational feasibility.

Authors’ Contributions

Y.Y.D. conceived the review, performed the literature search, organized the evidence, and drafted the manuscript. M.W. and D.W. supervised the study, provided overall guidance on the conception and structure of the review, and critically revised the manuscript. T.G. and M.H.S. contributed to literature collection, data organization, and manuscript revision. All the authors approved the final version of the manuscript.

Funding

This work was supported by the Peking University-Golden Resource Tengyun Clinical Research Program (project no. TY2025010), the Beijing Natural Science Foundation (project no. L252203), the Research and Development Foundation of Peking University People’s Hospital (project no. RDL2024-01), and the Beijing Health Technologies Promotion Program (project no. BHTPP2022007).

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Ethical Approval

Not applicable. This article is a narrative review of previously published literature and does not involve human participants, human data, or animal experiments.

Competing Interests

The authors declare no competing interests.