A Novel Dual-targeting OX40L and IL-13 Bispecific Antibody with Synergistic Effect for Atopic Dermatitis Treatment 2255160

Abstract

Abstract Introduction Atopic dermatitis (AD) is a chronic inflammatory skin disorder. While the immune response in AD is predominantly mediated by T-helper 2 (Th2) cells, contributions from Th1, Th17, and Th22 pathways are also significant. Interleukin-13 (IL-13), a key Th2 cytokine, promotes B-cell proliferation and goblet cell metaplasia. Concurrently, the OX40 ligand (OX40L) and its receptor OX40 function as critical co-stimulatory immune checkpoints regulating T-cell activation. Both the anti-IL-13 antibody lebrikizumab and the anti-OX40L antibody amlitelimab have shown clinical benefits in clinical. Dual targeting of IL-13 and OX40L may thus provide enhanced Th2 suppression and induce broad inhibition across T-helper subsets. Methods Binding affinity was quantified using ForteBio, while functional inhibition of downstream signaling was assessed via STAT6 and NF-κB luciferase reporter assays. Additionally, Mixed lymphocyte reaction (MLR) assay was employed to measure the secretion of IL-2, thymus and activation-regulated chemokine (TARC), IL-17A, and IL-22, serving as indicators of Th1, Th2, Th17, and Th22 activity, respectively. Finally, the in vivo efficacy was evaluated in a murine AD model. Results The bispecific exhibited high binding affinities to both IL-13 and OX40L. It also potently inhibited both STAT6 and NF-κB pathway activation. In MLR assays, the bispecific and the anti-OX40L antibody similarly suppressed the release of IL-2, IL-17A, and IL-22. Notably, the bispecific agent demonstrated superior inhibition of TARC release compared to either parental antibody alone. In vivo, the bispecific showed the highest therapeutic efficacy. Conclusion The anti—OX40/IL-13 bispecific exhibited enhanced suppression of Th1, Th2, Th17, and Th22 inflammatory responses both in vitro and in vivo, indicating synergistic immunomodulation through dual target engagement. These findings underscore its strong potential for future clinical development in the treatment of AD. Funding Source Nanjing Leads Biolabs Co., Ltd Topic Categories Therapeutic Approaches to Autoimmunity (THER)