P1114 Engineering and Development of a Novel Bispecific Antibody Targeting IL-23 and TL1A

Abstract Background Both IL23 and TL1A are clinically validated targets with genetical linkage to various human autoimmune diseases. Here we engineered and produced HXN-1003, a bispecific antibody (bsAb) simultaneously targeting both IL23 and TL1A, with the aim to further enhance clinical efficacy, and to overcome refractory and resistance associated with single-target based therapies. Methods The binding and blocking efficacy of HXN-1003 for each target were assessed using various in vitro assays, including IL23 reporter and mouse splenocyte activation assays for IL23, and TF-1 apoptosis and DR3-NFκB-Luc reporter assays for TL1A. The synergistic effect of dual targeting was measured by IL22 secretion in mouse splenocytes co-stimulated with IL23 and TL1A. In vivo efficacy was evaluated in hIL23/hTL1A transgenic mice with DSS-induced colitis and IMQ-induced psoriasis models, as well as in SD rats with subcutaneous injections of hTL1A and hIL23 to induce dermatitis. Results HXN-1003 features a tetravalent structure, with the anti-IL23 arm specifically binds to the p19 subunit of IL23, demonstrating superior affinity and blocking activity compared to benchmark Risankizumab. For TL1A, HXN-1003 binds to both the TL1A trimer and monomer with sub-nanomolar affinity, exhibiting similar blocking activity to its parent antibody HXN-1001 and RVT-3101. In the mouse splenocyte activation assay induced by IL23 and TL1A, HXN-1003 showed greater activity than each individual antibody and was equally active to their combination. In animal models, HXN-1003 significantly alleviated symptoms of DSS-induced colitis, and demonstrated superior therapeutic effects in the IMQ-induced psoriasis model compared to the IL23 monoclonal antibody. Additionally, in the dermatitis model induced by hTL1A and hIL23, the bsAb outperformed each individual antibody and their combination. Conclusion HXN-1003 simultaneously blocks IL23 and TL1A, with each arm exhibiting activity comparable to the parent monoclonal antibodies. It has demonstrated synergistic/additive therapeutic effects in both in vitro and in vivo experiments, highlighting its potential to enhance clinical efficacy and benefit autoimmune patients in multiple clinical settings.