Preclinical proof of principle for orally delivered Th17 antagonist miniproteins.
Berger Stephanie, Seeger Franziska, Yu Ta-Yi, Aydin Merve, Yang Huilin, Rosenblum Daniel, Guenin-Macé Laure, Glassman Caleb, Arguinchona Lauren, Sniezek Catherine, Blackstone Alyssa, Carter Lauren, Ravichandran Rashmi, Ahlrichs Maggie, Murphy Michael, Pultz Ingrid Swanson, Kang Alex, Bera Asim K, Stewart Lance, Garcia K Christopher, Naik Shruti, Spangler Jamie B, Beigel Florian, Siebeck Matthias, Gropp Roswitha, Baker David
Cell · 2024 · PMID 38936360 · 인용 90
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.