Preclinical proof of principle for orally delivered Th17 antagonist miniproteins

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. [Display omitted] •Computational design yielded low- and sub-pM minibinders of IL-17A and IL-23R•IL-23R minibinders are extremely resistant to heat, acid, and proteolysis•Oral IL-23R minibinder is as effective as a clinical mAb in mouse colitis De novo proteins can be computationally designed with sub-picomolar affinity and extreme stability to enable oral administration and were effective in a model of colitis.