B32-45 Discovery and Characterization of SIM0722, a Novel Half-life Extended Bi-specific Antibody Simultaneously Targeting TSLP and IL-13 for the Treatment of Chronic Respiratory Diseases

Abstract Rationale Thymic stromal lymphopoietin protein (TSLP) initiates allergic inflammation and IL-13 drives pathophysiological changes in airway and skin. Here we discovered and characterized SIM0722, a half-life extended bi-specific antibody simultaneously targeting both TSLP and IL-13, with the aim to further enhance clinical efficacy and improve patient’s compliance. Methods The binding activities to TSLP protein and IL-13 protein were determined by ELISA and SPR. SIM0722 was characterized through various in vitro assays, including TSLP-induced BaF3 cell proliferation and CCL17 release from PBMCs (for TSLP arm), IL-13 reporter assay, IL-13-induced TF-1 proliferation and IL-13 induced CD23 expression in PBMC assay (for IL-13 arm). The synergistic effect of dual-target blockade was investigated by CCL17 release in human PBMCs co-stimulated with TSLP and IL-13. Additionally, the in vivo synergistic effects of anti-TSLP and anti-IL-13 antibody were evaluated in a TSLP&IL-13-induced and OVA-induced asthma models in transgenic mice. Finally, the extended half-life was revealed in both human FcRn knock-in mice and non-human primate. Results SIM0722 simultaneously bound to both TSLP and IL-13 proteins with sub-nanomolar affinity and demonstrated superior functional activities under various functional assays on both TSLP and IL-13 axes compared to that of benchmark anti-TSLP mAb Tezepelumab and anti-IL13 mAb Lebrikizumab, respectively. SIM0722 also exhibited superior dual pathway blockade synergy in vitro in inhibiting CCL17 release over all publicly disclosed competitors, including Sanofi’s Lunsekimig analog, Teva/Biolojic’s BD9 analog, J&J/Proteologix’s PX128 analog. In vivo evaluation using an asthma model confirmed that anti-TSLP and anti-IL-13 combination alleviated asthmatic inflammation, with significantly reduced inflammatory cell infiltration and improved histological scores compared to either anti-TSLP or anti-IL-13 monotherapy. Moreover, SIM0722 showed encouraging PK profile with over 20 days half-life, which together with its excellent developability profile, may support extended dosing interval in the clinic with a patient-friendly subcutaneous formulation. Conclusions Taken together, these data support the further development of SIM0722 as a potential BIC therapeutic agent for the treatment of chronic respiratory diseases (CRSwNp, asthma, COPD ) with expected IND submission in 2026Q4. This abstract is funded by: None