TSLP AND IL-13 Dual Blockade By Lunsekimig Provides Broader Benefits On Type-2 Inflammation

<bold>Background:</bold> Asthma is a heterogeneous chronic disease with uncontrolled type-2 immune reactions and airway inflammation. Thymic stromal lymphopoietin protein (TSLP) initiates allergic inflammation and IL-13 drives pathophysiological changes in airway and skin. We speculate that TSLP synergizes with IL-13 to amplify allergic reactions. <bold>Objective:</bold> Test the hypothesis that dual blockade of TSLP and IL-13 represents an effective therapeutic strategy for asthma treatment. <bold>Methods:</bold> A bispecific anti-TSLP/IL-13 NANOBODY® compound (lunsekimig) antagonizing the function of these two soluble human cytokines was generated. PBMC and tissue-mimicing in vitro assays, and preclinical models were developed to study lunsekimig potency and benefits of dual targeting approach. <bold>Results:</bold> Primary lung epithelial cells derived from asthmatic subjects produced significantly higher levels of TSLP than those from healthy subjects. Transcriptomic analysis revealed that while TSLP and IL-13 stimulation alone promoted chemotactic activity and cell motility, respectively, combined cytokine signals triggered a synergistic response associated with antigen presentation and T-cell mediated inflammation. Indeed, lunsekimig was more potent in inhibiting TARC and eotaxin-3 production than targeting TSLP (tezepelumab) or IL-13 (lebrikizumab) alone in an allergen-stimulated triculture assay. Lunsekimig had significantly lowered plasma human IL­13 and TSLP levels, and inflammation in the PBMC-engrafted immunodeficient mice. <bold>Conclusion:</bold> These results support the hypothesis that a dual-targeting approach to TSLP and IL-13 inhibition may result in synergistic function and support the use of lunsekimig in human asthma clinical trials.