9MDZ

anti-IL23R VHH

9MDZ の概要

• エントリーDOI: 10.2210/pdb9mdz/pdb
• 分子名称: anti-IL23R VHH, GLYCEROL (3 entities in total)
• 機能のキーワード: ibd, inflammatory bowel disease, inflammation, immunology, immune system
• 由来する生物種: Lama glama
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13322.66

構造登録者

Kiefer, J.R.,Koerber, J.T.,Ota, N.,Davies, C.,Wallweber, H.A. (登録日: 2024-12-05, 公開日: 2025-05-21, 最終更新日: 2025-06-11)

主引用文献

Ota, N.,Davies, C.W.,Kang, J.,Yan, D.,Scherl, A.,Wong, A.,Cook, R.,Tao, X.,Dunlap, D.,Klabunde, S.,Mantik, P.,Mohanan, V.,Lin, W.,McBride, J.,Sadekar, S.,Storek, K.M.,Lupardus, P.,Ye, Z.,Ackerly Wallweber, H.,Kiefer, J.R.,Xu, M.,Chan, P.,Nagapudi, K.,Yi, T.,Koerber, J.T.
Engineering a protease-stable, oral single-domain antibody to inhibit IL-23 signaling.
Proc.Natl.Acad.Sci.USA, 122:e2501635122-e2501635122, 2025

PubMed Abstract: Interleukin (IL)-23 is a validated therapeutic target in inflammatory bowel disease. While antibodies targeting IL23 demonstrate clinical efficacy, they face challenges such as high costs, safety risks, and the necessity of parenteral administration. Here, we present a workflow to simultaneously enhance the affinity and protease stability of an inhibitory anti-IL23R VHH for oral use. Cocrystal structure analysis reveals that the anti-IL23R VHH employs both CDR and framework residues to achieve picomolar affinity for IL23R. The engineered VHH remains stable for over 8 h in intestinal fluid and 24 h in fecal samples. Oral administration of this VHH achieves deep pathway inhibition in a murine colitis model. Furthermore, a single pill provides sustained IL23R inhibition in nonhuman primate blood for over 24 h. With high potency, gut stability, high production yield, and favorable drug-like properties, oral VHHs offer a promising approach for inflammatory bowel diseases.

PubMed: 40434646
DOI: 10.1073/pnas.2501635122

実験手法

X-RAY DIFFRACTION (1.27 Å)