D1.443 - Preclinical Development of a Dual LIGHT/TL1A Bispecific Antibody

Fibrosis is the final consequence of chronic inflammatory responses, which progressively impair organ function, further exacerbate the disease, and may ultimately lead to patient death. Therefore, one of the major challenges in current therapeutic strategies is the effective simultaneous control of inflammation and reversal of fibrosis. TL1A and LIGHT, as members of the TNF superfamily, play crucial roles in triggering both inflammation and fibrosis. In this study, we developed a bispecific antibody (bsAb) HX15102 that simultaneously binds to and inhibits the functions of LIGHT and TL1A. This approach aims to effectively control or reverse fibrosis while suppressing inflammation, thereby significantly improving clinical outcomes.

The biological activity of the bispecific antibody (bsAb) was evaluated using multiple in vitro assays, including LIGHT–receptor blocking assays and LIGHT reporter assays to assess LIGHT activity, as well as TF-1 cell apoptosis assays and DR3–NF-κB–Luc reporter assays to evaluate TL1A activity. The synergistic effect of the bsAb was assessed by measuring NF-κB signaling pathway activation under co-stimulation with both LIGHT and TL1A.

HX15102 is a 2+2 structure bispecific antibody. HX15102 effectively blocks LIGHT from binding to its receptors (LTβR and HVEM) and inhibits LIGHT-mediated NF-κB signaling, demonstrating superior affinity and blocking activity to the benchmark Quisovalimab. For TL1A, HX15102 binds to the TL1A protein with sub-nanomolar affinity and exhibits blocking activity comparable to both its parental antibody and the benchmark antibody RVT-3101. In TF-1 reporter cells, HX15102 showed significantly greater efficacy in inhibiting NF-κB signaling activated by TL1A+LIGHT than either anti-TL1A monoclonal antibody (mAb) or anti-LIGHT mAb alone, with activity comparable to the combination of the two monoclonal antibodies. Further antigen-antibody complex testing revealed that HX15102 can simultaneously bind both TL1A and LIGHT without forming large complexes.

HX15102 simultaneously targets LIGHT and TL1A, with each binding arm exhibiting activity comparable to their respective parental monoclonal antibodies. The bispecific antibody demonstrates synergistic and/or additive therapeutic effects in in vitro experiments, highlighting its potential to enhance clinical efficacy and provide significant benefits to patients with autoimmune diseases in multiple clinical settings.