Engineering a protease-stable, oral single-domain antibody to inhibit IL-23 signaling

• 成果类型: Article
• 署名作者: Ota, Naruhisa; Davies, Christopher W.; Kang, Jing; Yan, Donghong; Scherl, Alexis; Wong, Anne; Cook, Ryan; Tao, Xun; Dunlap, Debra; Klabunde, Sha; Mantik, Priscilla; Mohanan, Vishnu; Lin, WeiYu; McBride, Jacqueline; Sadekar, Shraddha; Storek, Kelly M.; Lupardus, Patrick; Ye, Zhengmao; Wallweber, Heidi Ackerly; Kiefer, James R.; Xu, Min; Chan, Pamela; Nagapudi, Karthik; Xi, Tangshen; Koerber, James T.
• 署名单位: Roche Holding; Genentech; Roche Holding USA; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Genentech; Roche Holding USA; Roche Holding; Roche Holding USA; Genentech; Roche Holding; Roche Holding USA; Genentech
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11954
• DOI: 10.1073/pnas.2501635122
• 发表日期: 2025-06-03
• 关键词: nanobodies; antigen; innate; cells

摘要

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 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 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.