Background/Purpose: Inflammatory bowel disease (IBD) is a chronic, immune-mediated, inflammatory disease of the digestive tract. Several biological agents have greatly improved clinical course, remission, and complication rates in IBD patients. Ustekinumab, targeting p40 subunit, has demonstrated robust efficacy and approved for IBD. However, About 30% of patients are unresponsive to therapy , and 40% lose response over time,Therefore, more efficient therapies are needed. Recent studies showed that the Tumor necrosis factor-like cytokine 1A (TL1A) acts as a regulator of mucosal immunity and participates in immunological pathways involved in the IBD pathogenesis. Two anti-TL1A antibodies, MK-7240 and RVT-3101 have demonstrated excellent safety and effectiveness in patients with IBD. Therefore, a novel anti- TL1A/p40 bispecific antibody may hold promise in the treatment of autoimmune diseases including IBD.

Methods: An anti-TL1A monoclonal antibody was generated from mouse hybridoma and humanized by CDR grafting, then the anti-TL1A ScFv domain was fused to Ustekinumab using IgG1 Fc with LALAGA mutation. And YTE mutation was introduced to extend the half-life, creating the bispecific molecule: LBL-053. Binding affinity was assessed by Fortebio. The ligand-receptor interaction blocking capability of LBL-053 was evaluated by ELISA. The blocking efficacy of LBL-053 to TL1A and DR3 interaction was detected by reporter gene assay. The p40 and IL-12Rβ1 blocking efficacy was detected by ELISA and IFN-γ production inhibition assay .The synergistic effect of LBL-053 on TL1A and p40 was tested by IFN-γ production inhibition assay , which was conducted using CD4+T cells cocultured with TL1A, IL-12 , IL-18 proteins and the drug.IL-23 and TL1A induced ear inflammation mouse model was used to test the in vivo efficacy of LBL-053 in which ear swelling symptoms alleviating degree was recorded. Single dose PK study was conducted in humanized FcRn mice.

Results: LBL-053 antibody exhibited high binding affinity to human TL1A and IL-23 protein. It selectively blocked TL1A-DR3 interaction, leaving TL1A-DcR3 unaffected. The effect of LBL-053 on inhibiting TL1A-DR3 downstream signaling pathway was comparabile to RVT-3101, but better than MK-7240 and PF-07261271.LBL-053 also significantly blocked IL-23/IL-12Rβ1 interaction. The synergistic effect of LBL-053 on IFN-γ Inhibition using CD4+T cells with targeting IL-23 and TL1A pathway simultaneously demonstrated greater activity than each individual monoclonal antibody, their combination and PF-07261271.The effect of LBL-053 in relieving ear swelling symptoms was better than each individual monoclonal antibody and their combination. LBL-053 exhibited excellent PK profile in humanized FcRn mice.

Conclusion: LBL-053 showed dual immunosuppressive functions, simultaneously inhibiting TL1A-DR3 and IL-23/IL-12Rβ1 signaling pathway, indicating promising clinical applications for the treatment of autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lbl-053-a-novel-anti-tl1a-p40-bispecific-antibody-for-the-treatment-of-autoimmune-disorders/