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.
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.
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.
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.
Nanjing Leads Biolabs Co., Ltd
Therapeutic Approaches to Autoimmunity (THER)
Hui Yuwen, Hongyan Shang, Yan Zhu et al.· Journal of Immunology· 0 citations
Programmed cell death protein 1 (PD-1), an inhibitory immune checkpoint on T cells, maintains immune homeostasis. Dysregulated PD-1 signaling is implicated in autoimmune pathogenesis, whereas insufficient activity may result in uncontrolled T-cell responses. TNF-like ligand 1A (TL1A), a member of the TNF superfamily, engages DR3 to activate NF-κB pathway, thereby amplifying pro-inflammatory cytokine production and contributing to chronic inflammation and fibrosis. We developed a novel bispecific antibody that co-targets PD-1 and TL1A to achieve synergistic inhibition of pathogenic immune activation, with relevance to both PD-1 and TL1A driven immune disorders.
Bispecific antibodies were generated by fusing novel PD-1 agonistic and TL1A antagonistic VHH domains in a tetra-valent format. A series of candidates were evaluated through comprehensive in vitro assays including assessment of binding kinetics, PD-1/PD-L1/2 blocking, PD-1 agonism, TL1A-DR3 blocking, ADCC, and T-cell suppression. In vivo efficacy was assessed in a mouse colitis model.
The leading bispecific antibody binds to a unique PD-1 epitope, enhances PD-1—PD-L1/2 engagement, and inhibits TL1A—DR3 binding. It demonstrated dose-dependent PD-1 pathway agonism and TL1A antagonism, suppressing T-cell activation, proliferation and cytokine production. Robust ADCC activity against PD-1+ T cells was observed. In vivo, it showed superior efficacy over comparator monotherapies in ameliorating colitis.
The anti-PD-1xTL1A bispecific antibody exerts synergistic immunomodulation through three complementary mechanisms: enhancement of PD-1 inhibitory signaling, blockade of the TL1A—DR3 pathway, and selective depletion of PD-1-expressing T cells via ADCC. It significantly mitigates T-cell-driven inflammation in vitro and ameliorates disease activity in vivo, supporting its potential as a novel treatment for autoimmune diseases such as IBD (inflammatory bowel disease).
Nanjing Leads Biolabs Co., Ltd
Therapeutic Approaches to Autoimmunity (THER)
Hongyan Shang, Duqing Jiang, Xiao Huang et al.· Journal of Immunology· 0 citations
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