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 是自身炎症性疾病中经过充分验证的治疗靶点。针对IL-23和IL-17的抗体已显示出临床疗效，但受到成本高、安全风险、缺乏持续疗效以及需要肠胃外给药而给患者带来不便等限制。在这里，我们提出了设计的抑制 IL-23R 和 IL-17 的微型蛋白，其分子大小的一小部分具有类似抗体的低皮摩尔亲和力。这些微型结合剂可在体外有效阻断细胞信号传导，并且极其稳定，可实现口服给药和低成本制造。口服IL-23R微型结合剂在小鼠结肠炎中显示出比临床抗IL-23抗体更好的功效，并且在大鼠中具有良好的药代动力学（PK）和生物分布特征。这项工作表明，口服从头设计的微型粘合剂可以穿过肠上皮屏障达到治疗目标。从头设计的微型粘合剂具有高效力、肠道稳定性和简单的可制造性，是一种有前途的口服生物制剂形式。