Tavotek Biotherapeutics Co. Ltd.

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.

Thymic stromal lymphopoietin (TSLP) is a master regulator of allergic inflammation against pathogens at barrier surfaces of the lung, skin, and gut. However, aberrant TSLP activity is implicated in various allergic, chronic inflammation and autoimmune diseases and cancers. Biologics drugs neutralizing excess TSLP activity represented by tezepelumab have been approved for severe asthma and are being evaluated for the treatments of other TSLP-mediated diseases.

In this study, we discovered and characterized a novel humanized anti-TSLP antibody TAVO101 with high binding affinity to human TSLP, which blocks TSLP binding to its receptor complexes on cell surface. TAVO101 showed potent neutralization of TSLP activities in the TSLP-driven STAT5 reporter assay and cell proliferation assay. Results from ex vivo studies showed that TAVO101 neutralized TSLP-mediated CCL17 release from primary human CD1c+ dendritic cells and proliferation of activated CD4+ T cells. In addition, TAVO101 showed strong efficacy in both TSLP/OVA-induced asthma and imiquimod induced psoriasis models in hTSLP/hTSLPR double knock-in mice. We further conducted Fc engineering to optimize TAVO101 antibody with reduced affinity to Fcγ receptors and C1q protein but with increased affinity to FcRn receptor for half-life extension.

By recognizing a different epitope, similarly potent neutralization of TSLP activities, and longer circulating half-life than tezepelumab, novel anti-TSLP antibody TAVO101 offers a potential best-in class therapeutics for various TSLP-mediated diseases.