美国华盛顿大学David Baker和Stephanie Berger共同合作，近期取得重要工作进展。他们研究给出了口服Th17拮抗剂小蛋白的临床前原理证明。相关研究成果2024年6月26日在线发表于《细胞》杂志上。

据介绍，白细胞介素（IL）-23和IL-17是公认的自身炎症性疾病的治疗靶点。靶向IL-23和IL-17的抗体已显示出临床疗效，但由于需要胃肠外给药，因此受到高成本、安全风险大、缺乏持续疗效和患者方便性差的限制。

研究人员开发了抑制IL-23R和IL-17的迷你蛋白，它们能抑制 IL-23R 和 IL-17，具有类似抗体的低皮摩尔亲和力，而分子大小仅为原来的一小部分。该迷你结合剂在体外能有效阻断细胞信号传导，非常稳定，能够口服给药和低成本生产。口服给药的IL-23R迷你结合剂在小鼠结肠炎中表现出比临床抗IL-23抗体更好的疗效，并在大鼠中具有良好的药代动力学（PK）和生物分布特征。

总之，这一研究表明，口服新设计的迷你结合剂可以通过肠道上皮屏障达到治疗目标。凭借高效能、肠道稳定性和简单的可制造性，从头设计的迷你结合剂是一种很有前景的口服生物制剂。

附：英文原文

Title: Preclinical proof of principle for orally delivered Th17 antagonist miniproteins

Author: Stephanie Berger, Franziska Seeger, Ta-Yi Yu, Merve Aydin, Huilin Yang, Daniel Rosenblum, Laure Guenin-Macé, Caleb Glassman, Lauren Arguinchona, Catherine Sniezek, Alyssa Blackstone, Lauren Carter, Rashmi Ravichandran, Maggie Ahlrichs, Michael Murphy, Ingrid Swanson Pultz, Alex Kang, Asim K. Bera, Lance Stewart, K. Christopher Garcia, Shruti Naik, Jamie B. Spangler, Florian Beigel, Matthias Siebeck, Roswitha Gropp, David Baker

Issue&Volume: 2024-06-26

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.

DOI: 10.1016/j.cell.2024.05.052

Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00631-7