Preclinical Characterization of IBI3002, an Anti-IL-4Rα and Anti-TSLP Bispecific Antibody That Potently Dampens Inflammatory Response and Alleviates Asthma in Mice

Abstract Rational: IBI3002 is an innovative bispecific antibody currently in Phase I clinical development for asthma. In a bivalent format, it functions by potent co-blockade of IL-4Rα (both type I and type II receptors) and TSLP. This molecule is rationally designed to inhibit the key type 2 inflammatory cytokines IL-4 and IL-13 on different immune cells, airway smooth muscle cells, and epithelial cells, as well as TSLP that triggers downstream inflammatory responses. Collectively, IBI3002 aims to synergistically and broadly suppress both type 2 and the other types of inflammatory cytokines, which are correlated with eosinophilic and neutrophilic asthma. Method: in vitro binding and blocking activity of IBI3002 was assessed using human PBMC and DC/T cell co-culture systems. Importantly, we evaluated in-vivo efficacy in IL13-induced and OVA-induced asthma models in transgenic mice and performed head-to-head comparison with Lunsekimig as benchmark (IL13xTSLP). Results: IBI3002 binds human IL-4Ra and TSLP at picomolar levels and effectively inhibits IL-4, IL-13, or TSLP-induced CCL17 production in human PBMCs, with IC50 values of 0.09 nM, 0.02 nM, and 0.52 nM (these 3 numbers correspond to IL4, IL13, TSLP inhibition) respectively. The molecule also robustly suppresses type 2 cytokine production in DC/T cell co-culture. Additionally, IBI3002 synergistically blocks CCL17 production of human PBMCs co-stimulated with a mix of IL-4, IL-13, and TSLP. Importantly, in an OVA-induced asthma model with huTSLP/TSLPR/IL-4Rα/IL-4 tetra knock-in mice, IBI3002 significantly alleviates airway inflammation, evidenced by reduction in lymphocyte infiltration in the bronchoalveolar lavage fluid (BALF), including eosinophils, macrophages, and neutrophils, together with remarkable decrease of serum IgE levels. Notably, IBI3002 is more effective than Lunsekimig in IL13 induced asthma model. Furthermore, at lower drug exposure, IBI3002 demonstrates comparable in-vivo activity to Dupilumab and Tezepelumab, whose exposure was 4 to 9 times higher than that of IBI3002 individually. Conclusion: an innovative IL4RxTSLP bispecific antibody is characterized for its potent and synergistic inhibition of both IL4, IL13 and the upstream epithelial trigger TSLP. This molecule suppresses airway inflammation more potently than Dupixent, Tezepelumab and Lunsekimig even at lower concentration in-vitro or with lower exposure in-vivo. Therefore, IBI3002 can potentially bring broader and deeper clinical benefits to asthma patients of both high and med/low eosinophil counts.