Dual blockade of IL-18 and IL-4Rα by a bispecific antibody for improved treatment of atopic dermatitis
- 1Huanghe Science and Technology University, Zhengzhou, China
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 ILRalpha blockade alone. Interleukin18 (IL18), 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 IL18 neutralization and IL4Ralpha; 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 FJ0125, a bispecific antibody comprising human IL18 binding protein fused to a novel humanized anti IL4Ralpha 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 IL4/IL4Ralpha; knock in mice. Results: FJ0125 bound to IL18 and IL4Ralpha; with high affinity, engaged both targets, inhibited IL4/IL13 signaling with dupilumab comparable potency, and neutralized human and mouse IL18. In vitro, FJ0125 more effectively suppressed IL18 driven lymphocyte activation and type 1, type 2, and type 3 cytokine production than IL18BPFc or IL4Ralpha; monotherapy. In vivo, FJ0125 reduced multitype cytokines, improved dermatitis, lowered serum IgE, and abrogated the paradoxical IL22 increase observed with selective IL4Ralpha; blockade. Conclusion: Dual IL18/IL4Ralpha; blockade with FJ0125 achieves coordinated suppression of multitype inflammation and represents a mechanistically substantiated therapeutic strategy for AD.
Related
- A bispecific antibody targeting a membrane-proximal ASGPR1 region promotes TNF-α recruitment and uptake
- AD-REAL: A Prospective, Multinational, Observational Cohort Study of Clinical Effectiveness and Treatment Discontinuation of Oral Systemics for Moderate-to-Severe Atopic Dermatitis
- Treatment‐associated phenotype switching between psoriasis and atopic dermatitis
- Prophylactic treatment with broadly neutralizing antibody VRC01 selects for escape mutants after infection in Antibody-Mediated Prevention trials
- Successful treatment of anti-glomerular basement membrane antibody disease combined with membranous nephropathy using rituximab: a case report
BibTeX
@misc{zhang2026dual,
title = {{Dual blockade of IL-18 and IL-4Rα by a bispecific antibody for improved treatment of atopic dermatitis}},
author = {L. Zhang and Z. Meng and H. Bo and Y. Tian and W. Mou and X. Ping and J. Dong and Y. L. Li},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.11.758381},
url = {https://www.biorxiv.org/content/10.64898/2026.10.11.758381v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Dual blockade of IL-18 and IL-4Rα by a bispecific antibody for improved treatment of atopic dermatitis
AU - L. Zhang
AU - Z. Meng
AU - H. Bo
AU - Y. Tian
AU - W. Mou
AU - X. Ping
AU - J. Dong
AU - Y. L. Li
PY - 2026
DA - 2026/10/11
PB - bioRxiv
DO - 10.64898/2026.10.11.758381
UR - https://www.biorxiv.org/content/10.64898/2026.10.11.758381v1
AB - 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 ILRalpha blockade alone. Interleukin18 (IL18), 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 IL18 neutralization and IL4Ralpha; 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 FJ0125, a bispecific antibody comprising human IL18 binding protein fused to a novel humanized anti IL4Ralpha 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 IL4/IL4Ralpha; knock in mice. Results: FJ0125 bound to IL18 and IL4Ralpha; with high affinity, engaged both targets, inhibited IL4/IL13 signaling with dupilumab comparable potency, and neutralized human and mouse IL18. In vitro, FJ0125 more effectively suppressed IL18 driven lymphocyte activation and type 1, type 2, and type 3 cytokine production than IL18BPFc or IL4Ralpha; monotherapy. In vivo, FJ0125 reduced multitype cytokines, improved dermatitis, lowered serum IgE, and abrogated the paradoxical IL22 increase observed with selective IL4Ralpha; blockade. Conclusion: Dual IL18/IL4Ralpha; blockade with FJ0125 achieves coordinated suppression of multitype inflammation and represents a mechanistically substantiated therapeutic strategy for AD.
ER -