Bispecific and trispecific antibodies in atopic dermatitis: a review of the emerging clinical pipeline

1 Introduction

Biologics have transformed dermatologic care of atopic dermatitis (AD), with all currently approved agents designed as monospecific therapies that target a single molecule. Monospecific biologics are monoclonal antibodies engineered to bind one specific cytokine or receptor, thereby interrupting a single dominant inflammatory pathway. These agents act either against a soluble cytokine, such as IL-13 inhibition with tralokinumab or lebrikizumab, or against a soluble or membrane-bound receptor, such as IL-4Rα blockade with dupilumab or IL-31 receptor blockade with nemolizumab (Waligóra-Dziwak et al., 2024).

Despite their benefits, these monospecific biologics have not reliably delivered optimal disease control (or minimal disease activity) across the diverse AD patient population, revealing their incomplete effectiveness (Eichenfield et al., 2024).

In contrast, bispecific biologics are designed to bind two different targets at the same time within a single antibody, while trispecific biologics bind three. By blocking multiple inflammatory signals simultaneously, these agents expand pathway coverage using one molecule. This approach aims to achieve broader immune modulation similar to Janus kinase inhibitors, but through precise extracellular targeting rather than intracellular kinase inhibition, potentially preserving the specificity associated with biologic therapy (Brinkmann and Kontermann, 2017).

The AHEAD taskforce defines several optimal treatment targets for AD, including the achievement of Eczema Area and Severity Index 90 (EASI 90), Investigator’s Global Assessment 0/1 (IGA 0/1), and itch 0/1 on an 11-point numerical rating scale (NRS) from 0–10 (Silverberg et al., 2024). Simultaneous achievement of EASI 90 or IGA 0/1 with itch NRS 0/1 constitutes achieving minimal disease activity (MDA), which correlates with quality of life improvements. The introduction of monospecific biologics, particularly dupilumab, has transformed the management of moderate-to-severe AD, offering meaningful skin clearance, itch reduction, and quality-of-life improvements for many patients who previously relied on broad systemic immunosuppression. Yet registry data from TARGET-DERM highlight remaining gaps: despite substantial clinical benefit in many patients, a proportion do not consistently achieve these stringent benchmarks in real-world practice. Among patients at 12 months who failed to reach EASI-90 or itch NRS 0/1, approximately 80% were receiving dupilumab, likely reflecting its predominant use rather than a higher relative failure rate compared with other biologics. Thus, the disconnect lies not between treatment and improvement, but between meaningful response and the increasingly rigorous definitions of optimal disease control. In contrast, Janus kinase (JAK) inhibitors such as upadacitinib and abrocitinib have demonstrated higher rates of achieving optimal treatment targets, including in head-to-head clinical trials. The advantage of JAK inhibitors clinically in AD likely stems from their capability to inhibit simultaneously multiple cytokines across Th1, Th2, and Th17/22 pathways. This ultimately raises the standard of care for what therapies can deliver for AD patients (Blauvelt et al., 2021). Emerging early evidence supports this multi-specific strategy. In a first-in-patient randomized Phase 1/2a study, galvokimig, a trispecific antibody inhibiting IL-13, IL-17A, and IL-17F, demonstrated rapid and clinically meaningful efficacy in moderate-to-severe AD, with improvements observed as early as week 2 and ∼47% (43% placebo-adjusted) achieving EASI-90 at week 12 (Hunter et al., 2025). Moreover, galvokimig was engineered to bind albumin, leveraging FcRn-mediated recycling to reduce clearance, extend half-life, and enable less frequent dosing (Harmsen et al., 2024).

To close the efficacy gap between JAK inhibitors and monospecific biologics, the development of bispecific and trispecific biologics marks the next stage in therapeutic innovation. By expanding cytokine coverage while preserving biologic specificity and incorporating extended half-life engineering strategies, these next-generation constructs aim to match JAK inhibitor efficacy, yet provide less frequent dosing intervals. This offers a convenient option for patients who prefer injections.

Large protein biologics differ from small molecule drugs in their pharmacokinetics. As antibody-based molecules, their half-life is largely determined by interaction with the neonatal Fc receptor, which protects IgG from intracellular degradation and recycles it back into circulation, thereby extending systemic exposure (Roopenian and Akilesh, 2007). Half-life is typically measured by tracking the decline in serum drug concentrations over time and reflects systemic clearance, and tissue distribution (Wang et al., 2008). Advances in protein engineering, including Fc domain modifications and fusion strategies, can enhance FcRn engagement or reduce clearance to further prolong half-life (Strohl, 2018).

2 Brief overview of pathophysiology in atopic dermatitis

AD is driven by exaggerated Th2 inflammation arising from genetic and lipid-related defects in the epidermal barrier. Loss-of-function mutations in the filaggrin gene, which are crucial for keratin aggregation and skin hydration, increase epidermal permeability and transepidermal water loss. These barrier impairments permit environmental irritants and facilitate Staphylococcus aureus colonization, enabling allergens and microbes to penetrate the skin and trigger inflammation, including activation of kallikrein 5 and 7 proteases (Alvarenga et al., 2024; Hansen-Sackey and Hartono, 2025; Williams et al., 2017; Gallo and Horswill, 2024). Initially, damaged keratinocytes release alarmin cytokines, such as thymic stromal lymphopoietin (TSLP), IL-33, and IL-25, which activate local dendritic cells, Langerhans cells, and innate lymphoid cells, skewing the immune response toward a Th2 phenotype. These activated dendritic cells subsequently prime naïve T cells toward Th2 differentiation, guided by the surrounding alarmin and cytokine-rich environment (Yamamura et al., 2024). These Th2 cells subsequently secrete IL-4, IL-13, IL-5, and IL-31, which collectively drive the characteristic symptoms and clinical manifestations of AD.

2.1 Key cytokines

2.1.1 IL-4 and IL-13

IL-4 and IL-13 are the principal cytokines driving allergy-mediated AD (Table 1). IL-4 amplifies Th2 polarization and, together with IL-13, promotes B-cell class switching to IgE, which in turn activates mast cells and triggers histamine release, perpetuating the inflammatory cycle. Both cytokines signal through the type II IL-4 receptor and further impair epidermal integrity by downregulating filaggrin expression. Furthermore, they induce the chemokines CCL17 (TARC) and CCL22 (MDC), facilitating recruitment of Th2 cells into the skin, as well as CCL5, CCL11 (eotaxin-1), and CCL26 (eotaxin-3), which attract eosinophils, basophils, and additional T cells to inflammatory lesions. They also stimulate production of periostin and other matrix-associated factors, contributing to tissue remodeling and the development of chronic AD plaques (Haddad et al., 2022; Abdel-Mageed, 2025). Unlike IL-13, IL-4 also participates in early immune priming by signaling through the type I IL-4 receptor (Tollenaere et al., 2021). In contrast, IL-13 is more abundantly expressed than IL-4 in lesional AD skin, and its expression levels correlate closely with disease severity, making it an ideal target for treatment (Bieber, 2020). IL-13 is a key driver of chronic barrier disruption, keratinocyte reprogramming, and sustained lesional inflammation. As for itch, both IL-4 and IL-13 act on IL-4Rα/IL-13Rα1 receptors on sensory neurons and lower the itch threshold via TRP channels and JAK1-dependent signaling, causing increased pruritus (Meng et al., 2021).

TABLE 1. Brief overview of key cytokines in AD pathophysiology.

TSLP, Thymic stromal lymphopoietin; IFN-γ, Interferon gamma; Th1, T helper type 1 cells; Th2, T helper type 2 cells; Th17, T helper type 17 cells; Th22, T helper type 22 cells; ILC1, Group 1 innate lymphoid cells; ILC2, Group 2 innate lymphoid cells; NK, Natural killer cells; STAT1, Signal transducer and activator of transcription 1; STAT3, Signal transducer and activator of transcription 3; STAT6, Signal transducer and activator of transcription 6; JAK, Janus kinase; MHC, Major histocompatibility complex; OSMR, Oncostatin M receptor; IL-31RA, Interleukin-31 receptor alpha; ST2, Suppression of tumorigenicity 2.

2.1.2 IL-5

IL-5, while not specific to AD pathogenesis, is a key cytokine driving eosinophil activation and survival; eosinophils subsequently release cytokines and chemokines that amplify the inflammatory response in AD. This includes IL-4, IL-13, IL-6, IL-5 and granulocyte–macrophage colony-stimulating factor (GM-CSF) which sustain type 2 inflammation and perpetuate eosinophil recruitment and activation (Davoine and Lacy, 2014; Arnold et al., 2020-12; Rosenberg et al., 2013; Roufosse, 2018). In addition, eosinophils produce tumor necrosis factor-α (TNF-α), which promotes vascular activation and leukocyte infiltration, and transforming growth factor-β (TGF-β), which contributes to tissue remodeling and fibrosis in chronic AD lesions (Davoine and Lacy, 2014; Radonjic-Hoesli et al., 2021). Moreover, the eosinophils recruited by IL-5 release chemokines, such as CCL5 (RANTES), CCL11 (eotaxin-1), CXCL8 (IL-8), and CCL3 (MIP-1α), which recruit T cells, eosinophils, neutrophils, and mononuclear cells, thereby amplifying the inflammatory infiltrate in AD. These mediators act synergistically with the broader eotaxin family such as CCL24 and CCL26, which potently drive eosinophil chemotaxis, creating a reinforcing loop of eosinophil recruitment, activation, and sustained type 2 inflammation (Davoine and Lacy, 2014). IL-5 is not currently targeted by AD therapeutics.

2.1.3 IL-31

IL-31 is a key mediator of itch in AD and acts through the IL-31RA/oncostatin-M receptor (OSMR) complex directly on sensory neurons to amplify pruritic signaling (Łacwik et al., 2025). IL-31 also downregulates filaggrin and other differentiation/barrier genes and upregulates chemokines and antimicrobial peptides in keratinocytes, contributing to barrier dysfunction and inflammatory cell recruitment in AD skin (Jiang et al., 2020). In keratinocytes, IL-31 induces pro-inflammatory cytokines, IL-1α/β, IL-6, CCL17, CCL22, CCL18, CXCL1, and CXCL8, promoting recruitment of Th2 cells and other leukocytes. In eosinophils, as well as in eosinophil–keratinocyte co-culture systems, IL-31 further enhances the release of IL-1β, IL-6, CXCL1, CXCL8, CCL2, and CCL18, amplifying the inflammatory infiltrate characteristic of AD lesions (Cheung et al., 2010; Furue et al., 2018).

2.1.4 TSLP and IL-33

TSLP and IL-33 are epithelial alarmins released by damaged keratinocytes early in AD. TSLP activates dendritic cells and group 2 innate lymphoid cells (ILC2s) to promote Th2 differentiation, while IL-33 similarly stimulates ILC2s, Th2 cells, basophils, and mast cells to produce type 2 cytokines. Both cytokines are elevated in acute lesions, amplify local inflammation, and directly impair barrier function by reducing filaggrin expression, particularly through IL-33 (Alvarenga et al., 2024; Yamamura et al., 2024). The type 2 cytokine release by TSLP increases itch sensation, while IL-33 promotes nerve fiber growth and histamine-independent scratching (Łacwik et al., 2025; Guo et al., 2022; Turner and Zhou, 2014).

2.1.5 IL-22

In chronic or severe AD, IL-22 plays a critical role in keratinocyte hyperproliferation and epidermal thickening, contributing to the lichenified and acanthotic skin. It also suppresses keratinocyte differentiation and reduces expression of key barrier proteins such as filaggrin, similar to other cytokines, and involucrin, worsening epidermal dysfunction (Alvarenga et al., 2024). As such, IL-22 is correlated with disease severity and is associated with plaque-like AD (Laska et al., 2024). Moreover, IL-22 has been linked with not only head-and-neck AD, but also dupilumab-associated head and neck AD, both which demonstrate a pronounced Th22 and IL-22 immune signature (Bangert et al., 2024).

2.1.6 IL-17

Th17 cells produce IL-17 which contributes to rare AD endotypes and is associated with more psoriasiform, plaque-like features. IL-17 signaling, specifically IL-17A, promotes epidermal keratinocyte proliferation and induces proinflammatory mediators, including IL-6 and IL-8, as well as antimicrobial peptides that further amplify the response (Zhang et al., 2020; Johansen et al., 2016). Although more prevalent in psoriasis, this IL-17 skew in AD is most evident in Asian populations and in early-onset pediatric AD, where affected tissue demonstrates increased Th17-related markers despite preserved Th2 activation (Noda et al., 2015). IL-17F, frequently co-expressed with IL-17A, appears to have a less clearly established role in AD (Krzysiek et al., 2022). A pediatric genetic association study found no relationship between IL-17F polymorphisms and either AD susceptibility or disease severity (Esaki et al., 2016).

2.2 Key chemokines

Chemokines play a crucial role in the pathogenesis of AD. CCL17 (TARC) and CCL22 (MDC), induced by IL-4 and IL-13, are the main drivers. They recruit CCR4+ Th2 cells to the skin and are closely correlated with disease severity. CCL26 (Eotaxin-3) is a potent eosinophil attractant also upregulated by IL-4 and IL-13. CCL18 (PARC) recruits naïve T cells, while CCL27 (CTACK) recruits CCR10⁺ T cells perpetuating inflammation. IL-4 and IL-13 further induce CCL11 (Eotaxin-1) in dermal fibroblasts resulting in eosinophil infiltration. Eosinophils then interact with dermal fibroblasts to release CCL5 (RANTES) and CCL2 (MCP-1) which amplifies inflammation. Furthermore, CCL5 and CCL2 are induced by IL-31 and IL-33, promoting itch. CXCL8 (IL-8) is found to be elevated in the stratum corneum and contributes to neutrophil recruitment in mixed disease subtypes (Table 2) (Furue et al., 2019; Wong et al., 2012; Fujisawa et al., 2002; Pivarcsi and Homey, 2005; Gros et al., 2009).

TABLE 2. Brief overview of key chemokines in AD pathophysiology.

TARC, Thymus and activation-regulated chemokine; MDC, Macrophage-derived chemokine; RANTES, Regulated upon activation, normal T cell expressed and secreted; PARC, Pulmonary and activation-regulated chemokine; MCP-1, Monocyte chemoattractant protein-1; CTACK, Cutaneous T cell-attracting chemokine.

2.3 Mechanisms underlying pruritus

Pruritus in AD is largely histamine-independent, explaining the limited clinical benefit of conventional oral antihistamines. Instead, itch in AD arises from Th2 cytokines such as IL-31 and IL-4/IL-13 acting directly on sensory neurons, which express IL-4Rα/IL-13Rα1 and IL-31R. Specifically, IL-31 from Th2 cells and basophils activates itch-specific nerve fibers, while IL-4 and IL-13 lower the threshold for neuronal firing and promote nerve growth and branching in the skin, leading to increased itch sensitivity (Hansen-Sackey and Hartono, 2025). Furthermore, basophils release non-histaminergic pruritogens, including leukotrienes like leukotriene C4, which can directly activate C-fiber neurons. In contrast, mast cells contribute histamine and tryptase, playing a relatively larger role in acute urticarial-type itch than in chronic AD. Chronic scratching triggers release of neuropeptides such as substance P, which enhance inflammation and barrier damage, increasing keratinocyte alarmin release and further amplifying Th2-driven itch (Hansen-Sackey and Hartono, 2025).

2.4 Chronic AD

In acute AD, Th2-inflammation is considered the primary driver; however, with repeated flares, Th17 and Th1 pathways become increasingly activated and involved. In the chronic phase of AD, Th22 cells produce IL-22, which promotes keratinocyte hyperproliferation, epidermal thickening, and reduced expression of barrier proteins, while Th17 cells produce IL-17A and IL-17F and IL-22, further sustaining inflammation and contributing to tissue remodeling. Chronic AD, particularly in severe cases, often shows elevated IL-17 levels (Alvarenga et al., 2024; Hansen-Sackey and Hartono, 2025). Th1 pathways are characterized by cytokines such as interferon-γ and IL-12, which can aggravate keratinocyte injury and sustain inflammation (Alvarenga et al., 2024). Interferon-γ may also downregulate ceramide synthase (Tawada et al., 2014). These complex, overlapping pathways help explain why broad JAK inhibition, which dampens multiple cytokine signals including Th1 and Th2, may yield more complete skin clearance than IL-4/IL-13 blockade alone in moderate to severe chronic AD (Facheris et al., 2023).

3 Current limitations of single target therapies

While dupilumab inhibits IL-4 and IL-13 signaling, the antibody binds a single molecular entity in IL-4Rα; although single target biologics like dupilumab have led to meaningful improvements in disease signs and symptoms, many patients still experience inadequate responses (Silverberg et al., 2024). Clinical trials show that even among responders, symptoms such as pruritus, sleep disturbance, and impaired quality of life often persist (Silverberg et al., 2024). Importantly, mechanistic studies have revealed that patients who do not respond to IL-4Rα blockade often exhibit upregulation of alternate immune axes, including IL-17, IL-22, and interferon gamma (IFN-γ) (Czarnowicki et al., 2019). Registry data further confirm these limitations in real-world practice: in TARGET-DERM, ∼85% of patients failed to achieve the AHEAD-defined optimal treatment targets of IGA 0/1, EASI 90, or itch NRS 0/1 after 12 months of therapy, despite consistent dupilumab use (Eichenfield et al., 2024). These findings highlight the immunologic heterogeneity of AD and indicate that when one pathway is blocked, other cytokines compensate and continue driving disease activity. This overlap across inflammatory pathways explains why blocking a single cytokine or receptor is often insufficient for durable disease control, and why broader strategies such as multi-specific biologics may be necessary to achieve optimal treatment endpoints and/or MDA.

4 Rationale for multispecific approaches

The limitations of single target therapies and the mechanistic heterogeneity of AD create a strong rationale for developing multi-specific biologics. The heterogeneity of AD immune pathways, with upregulation of IL-17, IL-22, and IFN-γ in non-responders to IL-4Rα blockade, suggests that broader strategies targeting multiple cytokine axes may be needed to achieve durable control (Czarnowicki et al., 2019). Bispecific and trispecific antibodies represent one strategy, co-engaging multiple antigens to enhance pathway coverage and reduce reliance on a single inflammatory axis. Other platforms pair cytokine blockade with inhibition of immune cell activation receptors, enabling coordinated control of soluble cytokines and cellular signaling with the goal of restoring immune balance within a dysregulated network (Kabashima et al., 2019).

By combining mechanisms in a single therapy, multi-specific biologics may achieve faster onset and higher rates of response (skin clearance and itch relief), an effect demonstrated in oncology through advanced T lymphocyte (T-cell) engager models (Strohl, 2018). In dermatology, this approach directly addresses the inconsistent outcomes seen with single target biologics and offers the potential to reduce reliance on adjunctive medications (Kabashima et al., 2019). Importantly, the goal extends beyond clinical clearance alone: multi-specifics are designed to deliver meaningful improvements in patient experience, including itch relief, better sleep, and enhanced quality of life (Silverberg et al., 2024).

5 Structure and pharmacokinetics

5.1 Half-life extension

A key differentiating feature among next-generation multi-specific biologics is whether they incorporate half-life extension technologies. Most currently approved biologics, including dupilumab, have half-lives of approximately 20–28 days, necessitating biweekly or monthly dosing. Shorter half-lives require more frequent administration, which can negatively affect adherence and patient satisfaction, especially for injectables. Extending half-life is therefore a major goal among biologics, as it prolongs drug persistence in circulation, reduces injection frequency, and improves treatment convenience.

Mechanistically, half-life extension is most often achieved through engineering of the Fc region to enhance binding to the neonatal Fc receptor (FcRn). One well established approach is the YTE substitution (M252Y/S254T/T256E), which improves FcRn engagement and recycling, thereby prolonging serum persistence (Rolin et al., 2024). A second strategy involves Fc engineering or albumin binding formats, both of which further leverage FcRn-mediated recycling or exploit albumin’s naturally long half-life to extend antibody exposure (Tapia-Galisteo et al., 2023). Several extended half-life antibodies are already in clinical development for AD, including APG777, an IL-13 inhibitor, and IMG-007, an OX40 targeted agent, both of which demonstrate markedly prolonged half-lives compared with conventional biologics (Tapia-Galisteo et al., 2023-01). Of the multi-specific biologics currently in development, only a subset (e.g., APG279, TRIV-509/573, galvokimig, donzakimig) have disclosed half-life extension engineering, whereas many others have not. This represents a differentiating feature that may impact long term adoption and patient preference. Albumin binding is one such approach and is now being applied to multi-specific candidates such as galvokimig, which demonstrated prolonged half-life alongside encouraging efficacy in early clinical testing (Hunter et al., 2025). Whether coupling half-life extension with multi-pathway targeting will translate into optimal clinical outcomes and patient experience remains to be determined.

5.2 Fc receptor modulation

An additional engineering consideration for next-generation biologics is modulation of antibody-dependent cellular cytotoxicity (ADCC). ADCC occurs when Fc regions engage Fcγ receptors on immune effector cells, leading to target cell lysis (Booth et al., 2018). Some therapeutic antibodies exploit this mechanism, while others are specifically designed to minimize it and reduce off-target toxicity (Harmsen et al., 2024). Rocatinlimab (OX40), an afucosylated anti-OX40 antibody, enhances ADCC, a modification that has been linked to adverse events such as pyrexia, chills, and aphthous ulcers in clinical trials (Deng et al., 2024; Bunick, 2025). In contrast, IMG-007 incorporates an N297A Fc mutation to silence ADCC, and in a Phase 2a trial in AD, it was well tolerated with no reports of pyrexia or chills, and exhibited an extended half-life of approximately 31 days at therapeutic dose levels (Nimmerjahn and Ravetch, 2008). These contrasting strategies underscore the balance between therapeutic benefit and potential adverse effects.

6 Emerging clinical pipeline

A diverse therapeutic pipeline is advancing rapidly, including bispecific antibodies, trispecific antibodies, antibody cocktails, and nanobody-based constructs. These agents are designed to target well-established type 2 cytokines such as IL-4, IL-13, and IL-31, while also addressing emerging pathways implicated in sustaining disease activity, including OX40 and OX40 ligand (OX40/OX40L) signaling and serine proteases such as kallikrein 5 and kallikrein 7 (KLK5/7) (Kabashima et al., 2019; Shields et al., 2002; Guttman-Yassky et al., 2023). Several early phase clinical candidates have already entered trials, with oncology studies demonstrating that multi-specific formats can achieve favorable pharmacokinetics, reduced immunogenicity, and enhanced tissue penetration compared with traditional monoclonal antibodies (Strohl, 2018). Beyond AD, similar multi-specific platforms are being explored in psoriasis, asthma, and systemic autoimmune diseases, underscoring their potential as a versatile next-generation therapeutic class. Even within IL-13 targeting, different epitopes can be leveraged: for example, lebrikizumab binds an epitope ∼180^o opposite that of tralokinumab, and either epitope could be paired with another cytokine target (Bunick, 2025). These structural and thermodynamic distinctions between biologics are increasingly recognized as important drivers of clinical performance (Marfil-Cantón et al., 2024). This “mix and match” molecular strategy reflects the unprecedented diversity now emerging in multi-specific design. Figure 1 provides a visual overview of this pipeline, summarizing key cytokine targets, engineering strategies, and unique design features.

7 Multispecific antibodies

7.1 Dual neuroimmune itch and inflammatory blockade

7.1.1 NM26-2198 (JNJ-5939)

NM26-2198 is a bispecific antibody developed by Numab and J&J that targets IL-4Rα, inhibiting IL-4 and IL-13, along with IL-31 (Table 3). Similarly, dupilumab blocks the IL-4Rα alone and has shown significant disease reduction (Tsianakas et al., 2018). NM26-2198 aims to add greater suppression of itch through IL-31 signaling specifically. In patients with refractory pruritus, itch can further disrupt the epithelium and impair healing. As such, this dual approach targets type 2 inflammation, a key aspect of AD pathogenesis, but also itch in patients where monotherapy may not be effective (Figure 2). As of December 2025, Phase 2b trials have been terminated due to insufficient efficacy.

TABLE 3. Multispecific biologics under investigation for AD.

*NM26-2198 (JNJ-5939) terminated phase 2b trials as of December 2025 due to insufficient efficacy. Since submission of the manuscript, additional bispecific antibody programs have been disclosed, including Belenos’ BEL512 (TSLP/IL-13) and BEL536 (OX40L/IL-13), as well as an IL-13/OX-40L bispecific antibody program from EpimAb/Almirall. These developments occurred after the manuscript was originally submitted and were therefore not included in the original review. **ATTO-002 renamed to ATTO-3712. TSLP, Thymic stromal lymphopoietin; OX40L - OX40 ligand (tumor necrosis factor ligand superfamily member 4); KLK, Kallikrein-related peptidase; KLK5, Kallikrein-related peptidase 5; KLK7, Kallikrein-related peptidase 7; Th2, T helper type 2 cells; MoA, Mechanism of action; PK, Pharmacokinetics; Fc, Fragment crystallizable region; FcRn, Neonatal Fc receptor; IND, Investigational New Drug.

7.1.2 BBT001

BBT001, developed by Bambusa Therapeutics, is a bispecific biologic targeting IL-4Rα and IL-31, similar in concept to NM26-2198 (JNJ-5939) in its goal of broad type 2 immune modulation with simultaneous antipruritic activity. By engaging IL-4Rα, BBT001 is designed to inhibit IL-4 and IL-13 signaling, thereby reducing type 2 inflammation; simultaneous IL-31 neutralization is intended to reduce pruritus to a greater degree. The molecule has been engineered with an extended human half-life of approximately 33 days, possibly allowing for less frequent dosing relative to current IL-4Rα inhibitors such as dupilumab, which is typically administered every 2 weeks. In early clinical evaluation, a single dose produced sustained inhibition of pSTAT6, a key transcription factor downstream of IL-4/IL-13 associated with pro-inflammatory gene expression and barrier dysfunction in AD, for more than 8 weeks. In a Phase 1 study in healthy volunteers with low baseline inflammation, BBT001A also induced a dose-dependent reduction in CCL17 (TARC), a chemokine involved in Th2 cell recruitment. This biomarker modulation supports the concept that combined IL-4Rα and IL-31 blockade can achieve deeper suppression of type 2 inflammatory signaling than IL-4Rα inhibition alone, while simultaneously addressing itch to promote skin healing (Bambusa Therapeutics, 2025).

7.1.3 ZL-1503

Zai Lab’s preclinical agent ZL-1503 is a bispecific antibody that simultaneously targets IL-13 and the IL-31 receptor, thereby addressing both inflammatory and pruritogenic pathways in AD. As mentioned previously, IL-13 is a central effector cytokine in AD pathogenesis, and its selective blockade can substantially reduce disease burden while IL-31 is a key driver of chronic pruritus via direct effects on sensory neurons. As such, dual inhibition of IL-13 and IL-31 signaling is particularly favorable for patients with refractory itch, in whom ongoing scratching and barrier damage perpetuate inflammation despite treatment with other Th2-targeted biologics. In 3 nonhuman primate models, a single intravenous dose of ZL-1503 produced sustained pharmacodynamic inhibition of IL-13-mediated pSTAT6 signaling and scratching for at least 76 days, with some animals demonstrating inhibition for over 100 days (Zhang et al., 2025). Higher dose levels have been well tolerated in early studies, and the program is being advanced toward clinical evaluation in AD (The Derm Digest, 2025). It is now undergoing Phase 1b trials.

7.1.4 ATTO-002/ATTO-3712

ATTO-3712, developed by Attovia Therapeutics, is a bispecific Attobody molecule that targets IL-13 and IL-31 to address both Th2-driven inflammation and neurogenic pruritus in AD, similar in conceptual scope to ZL-1503. Distinct from conventional IgG-format bispecifics, ATTO-3712 leverages the small size and high-affinity, biparatopic design of the Attobody platform, which may enhance potency and tissue penetration, particularly within inflamed skin and peripheral nerve endings (Patchen, 2025). Clinically, it is intended for patients who continue to experience significant itch despite treatment with existing monotherapies such as IL-4Rα or IL-13 inhibitors. From a pharmacokinetic standpoint, Attobodies are modular and can be formatted into multispecific constructs with tunable half-lives ranging from hours to weeks, allowing ATTO-3712 to be optimized for dosing frequency and therapeutic setting (Attovia, 2024). It is now undergoing Phase 1 trials.

7.1.5 GB12-09

GB12-09, developed by Kexing Biopharma, is a bispecific antibody targeting IL-4Rα and IL-31Rα, to suppress type 2 inflammation and pruritus in AD at the level of the receptor. By binding IL-4Rα, GB12-09 inhibits IL-4/IL-13 signaling and reduces Th2-driven immune activation, while blockade of IL-31Rα prevents IL-31 ligand binding, attenuating neuronal itch. Uniquely, GB12-09 is an IgG single-chain Fv with VL-VH sequence optimization and stabilizing interchain disulfide bonds which enhance molecular stability and maintain bispecific functionality (Deng et al., 2024). Preclinical studies showed effective inhibition of IL-4, IL-13, and IL-31 pathways in vitro while animal studies demonstrated improvement of dermatitis-like symptoms, including reductions in serum IgE, IL-31 levels, skin inflammation, and scratching behavior (Deng et al., 2024). As such, GB12-09 exemplifies an emerging strategy for targeting AD pathogenesis that will need to be validated in clinical trials and translated to human disease before its therapeutic potential can be confirmed.

7.1.6 ZW1572

ZW1572, developed by Zymeworks, is a preclinical bispecific antibody that targets IL-4Rα and IL-31 for the treatment of AD. Unlike other similar therapies, the antibody utilizes Zymeworks’ Azymetric™ platform, which claims to engineer the antibody for native human IgG-like stability while ensuring low immunogenicity (Zymeworks Inc, 2025). By engaging IL-4Rα, it blocks signaling from both IL-4 and IL-13, suppressing type 2 inflammatory pathways. Inhibiting IL-31 further acts to reduce pruritus by interrupting activation of sensory neurons. ZW1572 aims to treat patients who experience persistent itch or incomplete symptomatic relief with IL-4/IL-13 directed monotherapies. Currently, it is under preclinical development and preliminary data is not yet publicly available (Zymeworks, 2025).

7.2 Combined alarmin and cytokine inhibition

7.2.1 PX128

PX128, developed by Proteologix in collaboration with Johnson and Johnson, is a bispecific antibody targeting TSLP and IL-13, two key cytokines along the Th2 inflammatory axis in AD (Proteologix, 2024). TSLP functions as an epithelial alarmin that initiates type 2 inflammation and promotes downstream IL-13 driven responses. As such, simultaneous blockade of both upstream TSLP and downstream IL-13 is expected to provide greater therapeutic efficacy by interrupting the pathway from its initiation through its effector phase. In experimental AD in Il13ra1-/- mice, dermatitis is driven by IL-13 signaling via the type II IL-4 receptor, whereas key immune outputs such as IgE induction and eosinophilia depend on IL-4 signaling via the type I IL-4 receptor. As such, IL-13-selective targeting may preserve IL-4/type I receptor-dependent functions (Liu, 2007; Bitton et al., 2020). This approach also aims to avoid excessive suppression of the broader Th2 network, which can theoretically promote a compensatory Th1 or Th17 skew and psoriasis-like inflammation; the IL-4Rα blocker dupilumab has been associated with new-onset psoriasis and arthralgia as noted by the FDA, as well as ocular surface complications. This underscores the rationale for selectively targeting the most pathogenic Th2 signals while preserving other immune axes.

7.2.2 SAR443765 (lunsekimig)

SAR443765 is a nanobody format bispecific developed by Sanofi targeting IL-13 and TSLP, aiming for deeper tissue penetration and broader Th2 pathway suppression. It utilizes a unique compact, pentavalent architecture composed of five linked domains ten times smaller than monoclonal antibodies at 12–15 kDa and includes an albumin-binding domain for half-life extension (Deiteren et al., 2024). This small format aims to enhance tissue penetration into inflamed skin and support high-concentration subcutaneous infrequent dosing. Combining anti-TSLP and anti-IL-13 therapies could potentially result in an additive effect, particularly against type 2 inflammation. Inhibiting TSLP prevents early alarmin activity initiating the inflammatory cascade while IL-13 inhibition aims to block Th2 mediated inflammation downstream. Furthermore, as TSLP is implicated in itch, its inhibition would likely reduce pruritus, maintaining barrier integrity and allow for improved skin healing. Although it is currently in Phase 2b development primarily for asthma, lunsekimig has completed preliminary human studies demonstrating acceptable safety and efficacy which could pave the way for evaluation in AD.

7.2.3 CM512

CM512, developed by Keymed Biotech, is an IgG-like bispecific antibody that simultaneously targets TSLP and IL-13, thereby combining upstream epithelial alarmin blockade and aspects of itch with downstream Th2 effector inhibition. In a Phase 1b study (n = 46) in China, CM512 patients received 300 mg or 600 mg or placebo treatments over 1 month, with the 300 mg group achieving EASI-75 rates of 50% compared to 7% in placebo at week six and 58% compared to 21.4% at week 12, and EASI-90 rates of 41.7% compared to 0% at week 12. These clinical improvements were sustained through week 24, approximately 20 weeks after the last dose, supporting the potential for long-interval dosing. Moreover, serum TSLP and IL-13 fell significantly after the initial dose along with TARC, eotaxin-3, CCL13, and IgE. The study reported a favorable safety profile (Belenos Biosciences, 2026). It is now undergoing Phase 2 trials.

7.2.4 ATI-052

ATI-052 (BSI-502), licensed by Aclaris Therapeutics from Biosion, is a bispecific monoclonal antibody that targets TSLP and IL-4Rα. By binding TSLP, it blocks upstream alarmin-driven signaling, while IL-4Rα binding inhibits downstream IL-4 and IL-13 signaling, attenuating the type 2 inflammatory response. The molecule is built on Biosion’s Flexibody® bispecific platform where its Fc region has been engineered for tighter neonatal Fc receptor (FcRn) binding with the goal of extending half-life and supporting infrequent dosing. In April 2025, the FDA cleared Aclaris’ IND for a randomized, blinded, placebo-controlled Phase 1a/1b trial of ATI-052 (Biosion, 2025).

7.2.5 PF-07264660

PF-07264660, a trispecific antibody developed by Pfizer, is designed to simultaneously inhibit IL-4, IL-13, and IL-33, targeting both adaptive Th2 signaling and upstream epithelial alarmin activity in AD. Unlike current IL-4Rα directed therapies which block receptor-mediated signaling of IL-4 and IL-13, PF-07264660 binds directly to the cytokine ligands themselves, while also incorporating an additional binding domain for IL-33. This triple-ligand strategy is intended to provide more comprehensive suppression of type 2 inflammation by covering the initiation phase of IL-33, which is released from stressed epithelium activating ILC2s and other innate cells, and the effector phase of IL-4 and IL-13, which drive main inflammatory response. PF-07264660 aims to offer deeper flare control as it works upstream, broader coverage of IL-33-driven phenotypes, and the convenience of a single multi-target biologic in one dose. Particularly in patients that do not respond well to IL-4/IL-13 blockade alone and continue to have disease from residual IL-33 activation, PF-07264660 may be an alternative. It is currently in Phase 2 development for moderate-to-severe AD (Pfizer Inc, 2025).

7.2.6 PF-07275315 (tilrekimig)

PF-07275315 (tilrekimig), another trispecific antibody from Pfizer, is designed to inhibit IL-4, IL-13, and TSLP, combining downstream Th2 cytokine blockade with upstream inhibition of an epithelial alarmin, similar to PF-07264660. Instead of targeting the IL-33 alarmin, tilrekimig targets TSLP, which is highly expressed in AD and is a key driver of dendritic cell activation and Th2 priming. TSLP inhibition may reduce flares by dampening initial immune recruitment, whereas IL-4/IL-13 blockade prevents further downstream inflammation, allergic responses, and barrier impairment as mentioned previously. Clinically, this could result in fewer flares, and improved barrier repair, potentially allowing for sustained disease control for longer periods of time (Pfizer Inc, 2025). Recent Phase 2 data showed that tilrekimig met its primary efficacy endpoint, demonstrating statistically significant improvements in EASI-75 at week 16 across all tested doses compared to placebo, with placebo-adjusted EASI-75 rates of 38.7%, 51.9%, and 49.4% across the low-, middle-, and high-dose groups, respectively. The agent was also well tolerated, with a favorable safety profile, and is expected to advance into Phase 3 development (Pfizer, 2026).

7.3 Barrier integrity and tissue remodeling

7.3.1 PX130

From Proteologix, PX130 targets IL-13 mediated Th2 skin inflammation and IL-22, a keratinocyte-acting cytokine that promotes epidermal hyperplasia, suppresses terminal differentiation, downregulates key barrier genes such as filaggrin and claudins, and whose tissue and serum levels correlate with AD severity (Laska et al., 2024; Facheris et al., 2023; Proteologix, 2024; Guttman-Yassky et al., 2018). PX130 is specifically designed for a subset of AD patients with chronic, lichenified lesions, where IL-22 is thought to contribute to skin thickening and persistent barrier disruption. By simultaneously inhibiting IL-13 and IL-22, PX130 aims to maintain or restore skin barrier integrity in these chronic cases while achieving durable disease control. Targeting IL-22 may further reduce and/or prevent head and neck AD, which has been shown to have elevated IL-22 over healthy controls (Bangert et al., 2024). In addition, the molecule is being engineered for infrequent dosing, a regimen that may be preferable for certain patient populations receiving biologic therapy (Alani et al., 2025). By focusing on downstream pathogenic cytokines, PX130 seeks to reduce inflammation and improve barrier function while avoiding broader cytokine blockade that could increase off-target effects or unwanted immunologic consequences.

7.3.2 Donzakimig (UCB-1381)

Donzakimig (UCB-1381) is a multispecific antibody developed by UCB that targets IL-13 and IL-22 and incorporates an albumin-binding domain to extend its half-life. Functionally, it combines IL-13 neutralization, which suppresses type 2 inflammation and allergic responses, with IL-22 blockade, which acts directly on epithelial cells to reduce epidermal hyperplasia, normalize keratinocyte differentiation, and improve skin barrier integrity. In AD, where elevated IL-22 levels are associated with thickened, lichenified lesions and marked barrier disruption, this dual mechanism is intended to address both immune-driven inflammation and its epithelial consequences. By concurrently inhibiting IL-13 and IL-22, donzakimig aims to improve clinical signs such as erythema and scaling while enhancing barrier function, potentially reducing transepidermal water loss, fissuring, and susceptibility to secondary infections. Similarly, IL-22 inhibition may further reduce and/or prevent head and neck AD (Bangert et al., 2024). Currently in early clinical development for moderate-to-severe AD, donzakimig represents a barrier-focused complement to galvokimig within UCB’s pipeline, with particular relevance for Th2/Th22-enriched, barrier-impaired disease phenotypes.

7.3.3 TRIV-509 and TRIV-573

TRIV-573, developed by Triveni Bio, is a trispecific antibody that combines inhibition of epidermal serine proteases kallikrein 5 and 7 (KLK5/7) with high-affinity IL-13 neutralization using a lebrikizumab-like epitope. Specifically, it binds the active enzymatic site of KLK5 and KLK7 and not allosteric sites. KLK5/7 are implicated in AD as they drive excessive degradation of barrier proteins, notably desmoglein-1 (DSG1), promote epidermal hyperplasia, and contribute to inflammation and itch (Chen et al., 2019). Its sister bispecific drug, TRIV-509, which inhibits KLK5/7 also through binding of the active enzymatic site rather than allosteric sites, demonstrated rapidly improved barrier integrity and epidermal differentiation with decreased parakeratosis and restored DSG1 expression by up to 3-fold in ex vivo AD patient skin (Andrus, 2025). It is now undergoing Phase 2 trials.

TRIV-573 builds on this and aims to address protease-driven barrier breakdown and neurogenic itch through KLK5/7, and Th2-mediated inflammation and allergic responses through IL-13. This may result in reduced external triggers by restoring skin barrier integrity while directly suppressing residual type 2 inflammation, benefiting patients who are partial responders to IL-4/IL-13 inhibition alone. Preclinical data indicate high affinity and extended half-life, supporting durable inhibition. Currently, TRIV-573 is undergoing Investigational New Drug (IND) studies (Triveni Bio, 2025).

7.4 Other molecules

7.4.1 Galvokimig

Developed by UCB, galvokimig targets IL-13 and IL-17A/F, making it one of the first to span type 2 and type 17 immunity, which may benefit patients with mixed endotypes. By inhibiting IL-13 using an epitope similar in location to tralokinumab, galvokimig suppresses type 2 inflammation of AD, while IL-17A/F blockade addresses Th17 subtypes which include epidermal hyperplasia and plaque-like changes. This Th2/Th17 subtype can be seen in chronic lichenified AD lesions, Asian patients, pediatric patients, or just idiopathically intrinsic (Noda et al., 2015; Esaki et al., 2016). A combined approach such as this is particularly favorable for such patients where pure Th2 inhibition may be insufficient. Furthermore, it has an added albumin-binding domain to extend its half-life and enable less frequent dosing. Early Phase 1/2a data in moderate-to-severe AD have shown improvements in Eczema Area and Severity Index (EASI) scores with an acceptable safety profile (UCB, 2025; Stanyon et al., 2025). It is now undergoing Phase 2b trials.

7.4.2 APG279

APG279, developed by Apogee Therapeutics, is a dual targeting antibody cocktail that combines two monoclonal antibodies: APG777, an anti-IL-13 antibody targeting a lebrikizumab-like IL-13 epitope, and APG990, an anti-OX40L antibody targeting an amlitelimab-like OX40L epitope. Inhibiting IL-13 reduces type 2–driven inflammation and barrier dysfunction, while blocking OX40L prevents binding with OX40 and modulates T-cell costimulation. In doing so, it induces T regulatory cells as opposed to Th2 cells found in AD. Moreover, OX40L is noted to be upstream of the IL-4/IL-13 pathway allowing for early suppression of the immune response. This strategy is intended to address both the acute cytokine milieu and the chronic T cell-mediated component of AD, with the potential for broader suppression of Types 1, 2, and 3 inflammation than single cytokine approaches. Both antibodies are engineered with long half-lives with APG777 at approximately 75 days and APG990 at approximately 60 days, enabling infrequent dosing. APG279 entered a Phase 1b trial against dupilumab in moderate-to-severe AD in 2025 (Nograles et al., 2025).

8 Challenges and future directions

Despite the promise of multi-specific biologics, important challenges remain. One issue is paradoxical head and neck dermatitis that develops in a subset of patients treated with dupilumab, often characterized by psoriasiform features and atypical histopathology (Shen et al., 2024). Mechanistic studies highlight that IL-22 signaling drives keratinocyte hyperplasia and psoriasis-like changes in AD, particularly in endotypes with mixed TH2/TH22/TH17 activation (Czarnowicki et al., 2019). Recent single cell gene expression studies of dupilumab associated head and neck dermatitis have shown suppression of type 2 pathways alongside a strong IL-22 immune signature, implicating this cytokine as a driver of these paradoxical clinical presentations (Wijs et al., 2020). Another uncertainty is whether next-generation, higher potency IL-4Rα inhibitors may unmask or contribute to cases of cutaneous T-cell lymphoma; to date, they have not. Furthermore, it remains to be seen whether multi-specific agents can address difficult to treat subsets of AD, such as chronic or recalcitrant hand eczema.

Emerging multi-specific biologics may also provide an important opportunity to refine our understanding of AD pathophysiology. Rather than simply expanding cytokine blockade, data from ongoing clinical trials will help clarify which inflammatory mediators are most critical to disease persistence and therapeutic response. AD reflects a complex immune imbalance involving Th2, Th22, and additional inflammatory pathways, and future studies may help define how restoring this balance leads to durable disease control (Weidinger and Novak, 2016; Guttman-Yassky et al., 2019). As these therapies are evaluated in clinical trials, their results may therefore inform not only treatment strategies but also the underlying biology of disease.

An additional challenge lies not in drug development but in real-world adoption. Many patients remain on ineffective therapy for extended periods, reflecting therapeutic inertia in dermatology where providers often hesitate to switch therapies even when optimal treatment targets are not met (Eichenfield et al., 2024). The central question remains whether multi-specific biologics can raise the standard of care beyond what existing JAK inhibitors and biologics have already achieved. Without demonstrating superior outcomes in skin clearance, itch relief, and quality of life, their clinical utility may remain limited.

Ultimately, the future of multi-specific biologics will depend on whether they can overcome both mechanistic uncertainties and real-world inertia to deliver clear, durable benefits. If these agents succeed in elevating patient outcomes, they have the potential to redefine treatment success and set a new standard of care for patients with AD.

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Footnotes

Edited by: Brian Poligone, Rochester Skin Lymphoma Medical Group, PLLC, United States

Reviewed by: Anna Zalewska-Janowska, Medical University of Lodz, Poland

Francisco José Navarro Triviño, San Cecilio University Hospital, Spain

Footnotes

AD, Atopic dermatitis; ADCC, Antibody dependent cellular cytotoxicity; CCL, Chemokine ligand; CXCL, CXC motif chemokine ligand; DSG1, Desmoglein 1; EASI, Eczema Area and Severity Index; FcRn, Neonatal Fc receptor; GM CSF, Granulocyte macrophage colony stimulating factor; IgE, Immunoglobulin E; IgG, Immunoglobulin G; IGA, Investigator Global Assessment; IL, Interleukin; ILC2, Group 2 innate lymphoid cell; IND, Investigational new drug; JAK, Janus kinase; KLK5/KLK7, Kallikrein related peptidase five and seven; MDA, Minimal disease activity; MoA, Mechanism of action; NRS, Numeric rating scale; OX40/OX40L, OX40 receptor and OX40 ligand; OSMR, Oncostatin M receptor; pSTAT6, Phosphorylated STAT6; PK, Pharmacokinetics; TARC, Thymus and activation regulated chemokine; TEWL, Transepidermal water loss; TGF β, Transforming growth factor beta; Th1/Th2/Th17/Th22, T helper cell subsets; TNF α, Tumor necrosis factor alpha; TSLP, Thymic stromal lymphopoietin; VL/VH, Variable light chain and variable heavy chain.