Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
Cell. 2024 Aug 8;187(16):4305-4317.e18. doi: 10.1016/j.cell.2024.05.052. Epub 2024 Jun 26.
Interleukin (IL)-23 and IL-17 are well-validated therapeutic targets in autoinflammatory diseases. Antibodies targeting IL-23 and IL-17 have shown clinical efficacy but are limited by high costs, safety risks, lack of sustained efficacy, and poor patient convenience as they require parenteral administration. Here, we present designed miniproteins inhibiting IL-23R and IL-17 with antibody-like, low picomolar affinities at a fraction of the molecular size. The minibinders potently block cell signaling in vitro and are extremely stable, enabling oral administration and low-cost manufacturing. The orally administered IL-23R minibinder shows efficacy better than a clinical anti-IL-23 antibody in mouse colitis and has a favorable pharmacokinetics (PK) and biodistribution profile in rats. This work demonstrates that orally administered de novo-designed minibinders can reach a therapeutic target past the gut epithelial barrier. With high potency, gut stability, and straightforward manufacturability, de novo-designed minibinders are a promising modality for oral biologics.
白细胞介素 (IL)-23 和 IL-17 是自身炎症性疾病的有效治疗靶点。针对 IL-23 和 IL-17 的抗体已显示出临床疗效，但由于成本高、安全性风险、疗效缺乏持久性以及患者便利性差（需要进行肠胃外给药）而受到限制。在这里，我们展示了设计的小分子蛋白，它们以抗体样的亲和力、低皮摩尔亲和力和分子大小的一小部分来抑制 IL-23R 和 IL-17。这些小分子结合物在体外能有效地阻断细胞信号转导，并且非常稳定，能够进行口服给药和低成本制造。口服给予的 IL-23R 小分子结合物在小鼠结肠炎中的疗效优于临床用的抗 IL-23 抗体，并且在大鼠中的药代动力学（PK）和生物分布特征良好。这项工作表明，口服给予的全新设计的小分子结合物可以穿过肠道上皮屏障到达治疗靶点。具有高效力、肠道稳定性和简单制造性的全新设计的小分子结合物是口服生物制剂的一种很有前途的方式。
