1776: Preclinical Development of a Novel TL1A-Targeting Antibody with Extended Half-life and Low Immunogenicity Risk for the Treatment of Inflammatory Diseases

Background/Purpose: Autoimmune and inflammatory diseases such as inflammatory bowel disease (IBD) and psoriasis are driven by dysregulated cytokine networks. TL1A, a member of the TNF superfamily, plays a key role in modulating inflammation and fibrosis through interaction with its cognate receptor, DR3. While anti-TL1A antibodies have shown promising efficacy in clinical trials, there remains a significant need for next-generation therapeutics with improved efficacy and safety, and more convenient dosing. Here, we describe the development and characterization of a humanized anti-TL1A antibody engineered for extended serum half-life and reduced immunogenicity risk. On this basis, a bispecific antibody targeting both TL1A and an orthogonal pathway such as IL-23 may offer synergistic benefits in alleviating IBD pathogenesis.

Methods: Humanized anti-human TL1A antibodies were derived from immune repertoire mining and optimized for pH-sensitive TL1A binding and FcRn-mediated IgG recycling. Binding to TL1A or related TNF superfamily members was assessed using surface plasmon resonance and ELISA, respectively. The formation of antibody-TL1A immune complexes was analyzed by negative-stain electron microscopy. Functional inhibition of TL1A signaling was evaluated using TF-1 cell apoptosis assay and human whole blood-based IFN-γ secretion assay. In vivo efficacy was assessed in a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model using human TL1A transgenic mice. Immunogenicity was evaluated by monitoring anti-drug antibody (ADA) responses in animal models. Serum half-life was examined in non-human primates following single-dose administration.

Results: The anti-TL1A antibody demonstrated epitope-specific pH-sensitive binding with human TL1A and cross-reactivity with cynomolgus TL1A, with no detectable binding to TNF-α or TRAIL. The antibody did not form large immune complexes when incubated with TL1A trimers in vitro, nor did it elicit ADA responses in animal models. It selectively inhibited TL1A/DR3 interaction while sparing TL1A/DcR3 binding, and effectively suppressed TL1A-induced TF-1 cell apoptosis and IFN-γ secretion in vitro. In the TNBS-induced mouse colitis model, the antibody exhibited a strong anti-inflammatory effect and alleviated disease symptoms. In non-human primates, the antibody showed an extended serum half-life compared to clinical-stage antibodies.

Conclusion: The humanized anti-TL1A antibody demonstrates high binding specificity and potent anti-inflammatory activity both in vitro and in vivo. The multi-objective antibody engineering confers extended half-life and low immunogenicity risk, supporting the potential for infrequent subcutaneous administration and improved safety. Further preclinical studies and development of a novel bispecific antibody targeting TL1A and an orthogonal inflammatory pathway are warranted.