Dual blockade of IL-18 and IL-4Rα by a bispecific antibody for improved treatment of atopic dermatitis
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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.
