P0848 Engineering and Development of a Novel Bispecific Antibody Targeting both TL1A and α4β7 for the Treatment of IBD

Abstract Background While single-target based therapies for IBD exhibit a significant "therapeutic ceiling," accumulating evidence suggests that multi-target combinatory approaches may provide better efficacy in certain clinical settings. HXN-1002 is a bispecific antibody (bsAb) simultaneously targeting both α4β7 and TL1A, aiming to further enhance clinical efficacy. Methods The binding and blocking efficacy of the bsAb for each target were assessed using various in vitro assays, including competitive ELISA and cell adhesion assays for α4β7, and TF-1 apoptosis and DR3-NFκB-Luc reporter assays for TL1A. The synergistic effect of the bsAb was further tested through target internalization and degradation. Subsequently, by using hα4β7/hTL1A transgenic mice, the in vivo efficacy of the bsAb was validated in a DSS-induced colitis model. Results HXN-1002 selectively binds to α4β7 but not α4β1, effectively blocking cell adhesion and activation mediated by MAdCAM-1, with activity comparable to Vedolizumab. For TL1A, HXN-1002 binds to both TL1A trimer and monomer with sub-nanomolar affinity, with similar blocking activity to its parental antibody HXN-1001 and RVT-3101. When HXN-1002 simultaneously binds to TL1A and cell surface-expressed α4β7, it significantly enhances internalization of α4β7, led to increased α4β7 degradation and decreased cell surface and total α4β7 expression. In addition, HXN-1002 treatment in the presence of TL1A results in a significantly delayed recovery of α4β7 expression, in comparison to the monospecific Vedolizumab. Studies show that pathological levels of TL1A in patients with various autoimmune disease are sufficient to promote the bsAb-mediated internalization and degradation of α4β7, leading to sustained downregulation of α4β7 expression. In a DSS-induced colitis model using hα4β7/hTL1A transgenic mice, the bsAb exhibited superior therapeutic effects compared to each individual monoclonal antibody. Conclusion HXN-1002 is a bsAb that simultaneously blocks the biological functions of α4β7 and TL1A, mediates a significantly enhanced α4β7 internalization and degradation, and is more efficacious than either individual monoclonal antibody or their combinations in both in intro and in vivo models. The bsAb has great potential to significantly enhance efficacy and overcome resistance to Vedolizumab in clinics. Preclinical and IND-enabling studies of the bsAb are currently underway.