D3.193 - Dual Blockade of TSLP and IL11 with a bispecific antibody: A Promising Strategy for the Treatment of Asthma and Other Airway Disorders

Asthma is a chronic inflammatory airway disease characterized by airflow obstruction and recurrent exacerbations, placing a significant burden on patients and healthcare systems. TSLP is a validated upstream epithelial cytokine that drives airway inflammation across both Th2-high and non-Th2 asthma phenotypes. In addition, IL11 is selectively expressed in eosinophils and airway epithelial cells in patients with moderate to severe asthma, with expression levels correlating with disease severity and airway remodeling. Given the complementary roles of TSLP and IL11 in airway inflammation and tissue remodeling, we hypothesized that simultaneous inhibition of both pathways could provide synergistic therapeutic benefit. Accordingly, we developed HX16118, a bispecific antibody targeting TSLP and IL11, to improve clinical outcomes in asthma and related airway diseases.

In a bleomycin-induced murine skin inflammation model, therapeutic efficacy was evaluated for anti-TSLP and anti-IL11 monoclonal antibodies (mAbs) administered either as monotherapies or in combination. Subsequently, a bispecific antibody HX16118 was engineered to simultaneously block TSLP and IL11. The in vitro potency of HX16118 was assessed using TSLPR/STAT5/Luc and IL-11R/STAT3/Luc reporter assays.

The results of the in vivo murine model demonstrated that both mAbs independently attenuated inflammation, as evidenced by reduced skin thickening and epidermal hyperplasia. Notably, combination treatment resulted in significantly stronger anti-inflammatory effects, suggesting a synergistic effect.  In the TSLP inhibition assay, HX16118 inhibited TSLP signaling with a sub-nanomolar IC₅₀, outperforming Tezepelumab. In classical IL11 signaling assays, HX16118 (IC₅₀ ~0.78 nM) exhibited significantly higher potency than HB0056, showing comparable activity to 9MW3811 (~1.27 nM). Importantly, in hyper-IL11 trans-signaling assays, HX16118 (IC₅₀ ~1.04 nM) displayed markedly enhanced potency compared to both HB0056 and 9MW3811 (~18.60 nM). Multiple in vivo efficacy studies of HX16118 are currently ongoing using clinically relevant animal models.

These results indicate that TSLP and IL11 synergistically promote the progression of inflammatory diseases, and that simultaneous inhibition of both signaling pathways produces a synergistic therapeutic effect. Accordingly, HX16118 holds strong potential for the treatment of asthma and other inflammatory airway diseases. Preclinical development of HX16118 is currently underway.