P0835 AI-guided generation and development of HXN-1001, a highly potent and half-life extended anti-TL1A antibody

Abstract Background TL1A, a member of the TNF family, is genetically associated with several human autoimmune diseases, including IBD, psoriasis, and RA. TL1A-blocking antibodies have demonstrated clinical efficacy in patients with UC and CD. HXN-1001 is a novel humanized anti-TL1A antibody with strong blocking activity and extended in vivo half-life. Methods Affinity for soluble TL1A was assessed using SPR, while binding to membrane TL1A was measured with flow cytometry. The activity of HXN-1001 was validated through various in vitro experiments, including blocking TL1A binding to DR3-overexpressing cells, TL1A-induced TF-1 apoptosis, DR3-NFκB-Luc reporter assays, and IFN-γ release from primary T cells. In vivo efficacy was demonstrated in DSS-induced colitis and IMQ-induced psoriasis models using hTL1A, hTL1A/hα4β7, or hTL1A/hIL23 transgenic mice. The in vivo half-life was studied in hFcRn transgenic mice and rhesus monkeys. Results HXN-1001 is a humanized antibody that binds to TL1A via unique epitopes, exhibiting sub-nanomolar affinity for both TL1A trimer and monomer. It shows significantly stronger binding to TL1A-overexpressing cells compared to MK-7240 and RVT-3101. HXN-1001 effectively inhibits TL1A-induced NF-κB activity, apoptosis of TF-1 cells, and IFN-γ secretion in human primary T cells, with superior potency to both RVT-3101 and MK-7240. In a DSS-induced colitis model in transgenic mice, HXN-1001 demonstrated superior anti-inflammatory effects compared to RVT-3101, MK-7240, and the α4β7 antibody Vedolizumab. In an IMQ-induced psoriasis model, HXN-1001 exhibited better therapeutic effects than the marketed anti-IL-23 monoclonal antibody Risankizumab. The in vivo half-life of HXN-1001 is approximately 18 days in Tg32 hFcRn-transgenic mice and 23 days in Rhesus monkeys, supporting a clinical dosing frequency of at least every 8 to 12 weeks or even longer. Conclusion HXN-1001 is a next-generation antibody targeting TL1A, offering significant advantages in efficacy and in vivo half-life. It has strong potential to enhance clinical efficacy and dosing convenience. HXN-1001 is anticipated to enter clinical development in Q2 2025.