Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
Eur J Pharmacol. 2018 Jun 5;828:89-96. doi: 10.1016/j.ejphar.2018.03.036. Epub 2018 Mar 26.
Interleukin (IL)-12 and IL-23 share a common subunit (p40) and function in T-helper (Th) 1 and Th17 immunity, respectively. Anti-IL-12/23p40 and specific anti-IL-23 antibodies are currently in clinical use for psoriasis and undergoing trials for autoimmune diseases. Since expression levels of the IL-23 receptor are likely to be much lower than those of IL-23, an anti-IL-23 receptor antibody might offer greater promise in inhibiting the IL-23-IL-17 pathways involved in inflammatory disorders. To our knowledge, no anti-IL-23 receptor antibody has been trialed in clinical studies to date. This study describes the generation and characterization of AS2762900-00, a fully human monoclonal antibody against the IL-23 receptor. AS2762900-00 bound both human and cynomolgus monkey IL-23 receptors. AS2762900-00 showed potent inhibitory effects on IL-23-induced Kit-225 cell proliferation compared to the existing anti-IL-12/23p40 antibody, ustekinumab. In a single dose administration pharmacodynamics study in cynomolgus monkeys, 1 mg/kg of AS2762900-00 significantly inhibited (> 85%) IL-23-induced STAT3 phosphorylation in blood for up to 84 days. Therefore, AS2762900-00 represents a potent novel IL-23-IL-17 pathway inhibitor with the potential to be developed into a new therapy for the treatment of autoimmune diseases.
白细胞介素 (IL)-12 和 IL-23 共享一个共同的亚基 (p40)，分别在辅助性 T 细胞 (Th)1 和 Th17 免疫中发挥作用。抗 IL-12/23p40 和特异性抗 IL-23 抗体目前用于治疗银屑病，并正在进行自身免疫性疾病的临床试验。由于 IL-23 受体的表达水平可能远低于 IL-23，因此抗 IL-23 受体抗体在抑制参与炎症性疾病的 IL-23-IL-17 途径方面可能更有希望。据我们所知，迄今为止，尚无抗 IL-23 受体抗体在临床试验中进行过试验。本研究描述了 AS2762900-00 的产生和特性，AS2762900-00 是一种针对 IL-23 受体的完全人源单克隆抗体。AS2762900-00 与人及食蟹猴的 IL-23 受体结合。与现有的抗 IL-12/23p40 抗体 ustekinumab 相比，AS2762900-00 对 IL-23 诱导的 Kit-225 细胞增殖具有更强的抑制作用。在食蟹猴单次剂量给药的药效学研究中，1mg/kg 的 AS2762900-00 可显著抑制 (>85%)IL-23 诱导的血液中 STAT3 磷酸化长达 84 天。因此，AS2762900-00 代表了一种新型强效的 IL-23-IL-17 途径抑制剂，具有开发为治疗自身免疫性疾病的新疗法的潜力。
