Preclinical proof of principle for orally delivered Th17 antagonist miniproteins - Institut Pasteur Accéder directement au contenu
Article Dans Une Revue Cell Année : 2024

Preclinical proof of principle for orally delivered Th17 antagonist miniproteins

David Baker
  • Fonction : Auteur correspondant

Résumé

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.
Fichier principal
Vignette du fichier
1-s2.0-S0092867424006317-main.pdf (6.87 Mo) Télécharger le fichier
Origine Publication financée par une institution
Licence

Dates et versions

pasteur-04634051 , version 1 (03-07-2024)

Licence

Identifiants

Citer

Stephanie Berger, Franziska Seeger, Ta-Yi Yu, Merve Aydin, Huilin Yang, et al.. Preclinical proof of principle for orally delivered Th17 antagonist miniproteins. Cell, In press, ⟨10.1016/j.cell.2024.05.052⟩. ⟨pasteur-04634051⟩

Collections

PASTEUR
0 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More