Dual blockade of IL-18 and IL-4Rα by a bispecific antibody for improved treatment of atopic dermatitis
Year: 2026
Type: preprint
Abstract: Background Atopic dermatitis (AD) is a chronic inflammatory dermatosis primarily driven by type 2 immunity, with additional type 1 and type 3 components that may limit the benifit of IL-4Rα blockade alone. Interleukin-18 (IL-18), an epithelial alarmin genetically associated with AD and correlated with disease severity, has been implicated as an upstream amplifier of this mixed inflammatory response. Objective To assess whether concurrent IL-18 neutralization and IL-4Rα blockade with a bispecific antibody provides broader and more balanced suppression of AD-relevant type 1, type 2, and type 3 pathways than single-target inhibition. Methods We generated FJ-0125, a bispecific antibody comprising human IL-18 binding protein fused to a novel humanized anti-IL-4Rα antibody, and characterized its binding, signaling, and functional activity in vitro and in vivo. The activity was evaluated in human group 2 innate lymphoid cell and primed Th2 cell assays, a keratinocyte–dendritic cell–T cell coculture system, and an MC903/Staphylococcus aureus–induced dermatitis model in human IL-4/IL-4Rα knock-in mice. Results FJ-0125 bound to IL-18 and IL-4Rα with high affinity, engaged both targets, inhibited IL-4/IL-13 signaling with dupilumab-comparable potency, and neutralized human and mouse IL-18. In vitro, FJ-0125 more effectively suppressed IL-18–driven lymphocyte activation and type 1, type 2, and type 3 cytokine production than IL-18BP-Fc or IL-4Rα monotherapy. In vivo, FJ-0125 reduced multitype cytokines, improved dermatitis, lowered serum IgE, and abrogated the paradoxical IL-22 increase observed with selective IL-4Rα blockade. Conclusion Dual IL-18/IL-4Rα blockade with FJ-0125 achieves coordinated suppression of multitype inflammation and represents a mechanistically substantiated therapeutic strategy for AD. Highlights FJ-0125 is a bispecific antibody fusing IL-18 binding protein to anti–IL-4Rα. FJ-0125 neutralizes IL-18 and blocks IL-4/IL-13 signaling with high potency. Dual blockade broadly suppresses type 1, 2, and 3 inflammation in vitro. FJ-0125 outperforms dupilumab in an MC903/S. aureus dermatitis model. FJ-0125 prevents the IL-22 rebound seen with selective IL-4Rα blockade.
Language: English
Subfield: Dermatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7222885880