LB1039 New Insights into Neuronal Itch Mechanisms by Targeting IL-13Rα1 with Eblasakimab

Chronic itch is a cardinal feature of multiple type-2 driven skin disorders exemplified by atopic dermatitis (AD). The signaling of itch in AD has been recently postulated to be amplified by the inflammatory cytokines present within the skin. In inflammatory skin diseases, cytokines exacerbate the immune responses, disrupt the skin barrier, and drive the disease pathology. The direct neuronal activation by type-2 canonical cytokines was first described with Interleukin-31 (IL-31). Recently, it has been shown that IL-13 acts as a neuronal enhancer for a multitude of different itch pathways in human neurons. Our objective is to understand the relevance of targeting the IL-13 receptor alpha 1 (IL-13R α1), on human sensory neurons and how this might result in cellular and intracellular changes altering neuronal activity. To study these phenomena, we used eblasakimab, a monoclonal human IgG4 antibody, which binds to the human IL-13Rα1 with nanomolar affinity. By binding to the receptor, eblasakimab prevents signaling of IL-4 and IL-13 through the type-2 receptor, which is expressed on a multitude of different immune and non-immune cells except for T-cells. Using an ex-vivo human neuronal model system, human dorsal root ganglia (hDRG) neurons were treated with IL-4 or IL-13 alone, or in combination, and were subsequently subjected to pruritogens. Neuronal responses were captured by live cell calcium imaging. Our data with human sensory neurons pre-stimulated with IL-4, IL-13 and their combination showed a neuronal enhancer effect for IL-4, and IL-13 with no obvious synergy or combined additive enhancer effects on pruritic pathways. Eblasakimab significantly reduced neuronal responses to IL-4, IL-13, and their combination by more than 40% to control conditions (p = 0.0001). Moreover, our finding that eblasakimab treatment reduced neuronal responses below vehicle group suggests that IL-13Rα1 has an additional role in neuro-immune modulation beyond the cytokine-related neuronal itch sensitization in inflammatory diseases.