PDF(Pubmed)
Abstract：
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.
摘要：
白细胞介素（IL）-23和IL-17是自身炎性疾病中经过充分验证的治疗靶标。针对IL-23和IL-17的抗体已显示出临床疗效，但受到高成本的限制。安全风险,缺乏持续的疗效，和差的病人方便，因为他们需要肠胃外给药。这里,我们提出了设计的小蛋白抑制IL-23R和IL-17的抗体样，在分子大小的一小部分低的皮摩尔亲和力。小结合剂在体外有效阻断细胞信号传导，并且非常稳定，使口服给药和低成本制造。口服施用的IL-23R小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,并且在大鼠中具有有利的药代动力学(PK)和生物分布特征。这项工作表明，口服给药的从头设计的小结合剂可以通过肠道上皮屏障达到治疗目标。具有很高的效力，肠道稳定性，和简单的可制造性，从头设计的微型粘合剂是口腔生物制剂的一种有前途的方式。
