ASP7266, a Novel Antibody against Human Thymic Stromal Lymphopoietin Receptor for the Treatment of Allergic Diseases

Abstract

Thymic stromal lymphopoietin (TSLP), positioned at the top of the inflammatory cascade, is a key regulator that enhances allergic inflammatory responses by activating T helper type 2 cells, Group 2 innate lymphoid cells (ILC2), and myeloid dendritic cells (mDCs) via the TSLP receptor (TSLPR). We evaluated the inhibitory effects of ASP7266, a novel recombinant fully human IgG₁ monoclonal antibody against TSLPR, on TSLP signaling and inflammation. The inhibitory effects of ASP7266 and the control antibody tezepelumab on TSLP and TSLPR interactions were investigated using a proliferation assay with TSLP stimulation and a chemokine production assay. The pharmacological effects of ASP7266 were investigated by examining differentiation of naive CD4⁺ T cells, ILC2 cytokine production, and ascaris extract-induced skin allergic reaction in cynomolgus monkeys. ASP7266 potently inhibited TSLP-induced cell proliferation and C-C motif chemokine ligand 17 production. Furthermore, ASP7266 inhibited TSLP-stimulated mDC-mediated naive CD4⁺ T-cell differentiation and interleukin 5 production by lineage-negative peripheral blood mononuclear cells, which can be considered ILC2 in vitro. In sensitized monkeys, ASP7266 completely suppressed ascaris extract-induced allergic skin reactions. Based on these results, ASP7266, a novel human therapeutic antibody against TSLPR, is a potential therapy for patients with allergic diseases. SIGNIFICANCE STATEMENT: TSLP, positioned at the top of the inflammatory cascade, plays a key role in various allergic diseases, including asthma, chronic rhinosinusitis with nasal polyposis, and atopic dermatitis. Here we show that the anti-TSLPR antibody ASP7266 exhibited excellent pharmacological activity in preclinical studies. Therefore, ASP7266 has the potential to be a promising treatment option for patients with allergic disorders.