ES302, A Novel TL1A/IL-23p19 Bi-specific Antibody Demonstrates Robust Efficacy and Developability for Inflammatory Bowel Disease 2305836

Abstract

Abstract Introduction The TL1A/DR3 and IL-23 pathways exhibit well-documented synergy in driving chronic intestinal inflammation, with TL1A enhancing IFN-γ and IL-17 production in a T cell-intrinsic manner and IL-23 stabilizing the Th17 lineage. We hypothesize that simultaneously co-targeting these two non-redundant axes with a single bispecific agent will deliver superior efficacy by fundamentally reshaping the dysregulated immune landscape in conditions like inflammatory bowel disease (IBD). Methods We developed a fully human, symmetric 1 + 1 IgG-formatted BsAb. And the Fc portion was engineered to extend serum half-life. Binding affinity for both TL1A and IL-23p19 were determined by surface plasmon resonance (SPR). The dual functionality was assessed using cell-based reporter assays: Inhibition of TL1A-induced NF-κB activation and IL-23-induced STAT3 phosphorylation as well as IL17 secretion from PBMCs. The immune complex formation was assessed by SEC-MALS. In vivo efficacy was determined in human TL1A/IL-23 KI mice using TNBS-induced colitis model. Developability was assessed and PK profile was evaluated in FcRn transgenic mice. Results The ES302 demonstrated high-affinity binding to both targets. It potently neutralized both TL1A and IL-23 functionality from in vitro assays. In animal model, the ES302 showed significantly superior efficacy over monospecific therapies, markedly reducing disease activity, histopathological scoring, and pro-inflammatory cytokines. The molecule exhibited low immunogenicity risk, and excellent developability properties, including high Tm value, low viscosity, and superior stability under stress conditions, compatible with high-concentration formulation for subcutaneous administration. Furthermore, ES302 exhibited excellent PK profile (e.g. very long in vivo half-life) in humanized FcRn mice and NHP. Conclusion ES302 is a highly differentiated antibody with strong potential for the treatment of inflammatory bowel diseases. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)