Abstract
Thymic stromal lymphopoietin (TSLP) works synergistically with Th2 cytokines to regulate infection, inflammation, and metabolic homeostasis. However, their aberrant activities lead to the onset and sustaining of many types of allergic inflammatory diseases. While biologics drug molecules blocking either TSLP or IL-4/IL-13 show clinical efficacies, the broader effect of simultaneously targeting these cytokines remains to be explored. We generated a bispecific antibody (BsAb) targeting both TSLP and IL-4Rα, which effectively blocked the signaling cascades driven by TSLP, IL-4, and IL-13. The BsAb also neutralized TSLP-driven CD4(+) T cell proliferation as well as IL-4 and IL-13-driven TF-1 cell proliferation. The BsAb reduced CCL17 release from CD14(+) monocytes activated by LPS, TSLP, and IL-4 and reduced allergen-induced CCL26 and IL-5 release from co-cultures of PBMC, MRC-5, and A549 cells. In a TSLP/OVA-induced asthma model with transgenic human TSLP, TSLP receptor, IL-4, and IL-4Rα mice, the BsAb reduced every single allergic/inflammatory hallmark, while the single target blockade antibody failed to have such comprehensive effects. Our data suggested that simultaneous blocking of TSLP, IL-4, and IL-13 could offer broader control of allergic inflammation, which could translate to a more effective treatment of related disorders.