Engineering a protease-stable, oral single-domain antibody to inhibit IL-23 signaling
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (25)
Naruhisa Ota
Department of Immunology Discovery, Genentech
Christopher W. Davies
Antibody Engineering, Genentech
Jing Kang
Translational Immunology, Genentech
Donghong Yan
Translational Immunology, Genentech
Alexis Scherl
Pathology, Genentech
Anne Wong
Biochemical and Cellular Pharmacology, Genentech
Ryan Cook
Biochemical and Cellular Pharmacology, Genentech
Xun Tao
Preclinical and Translational Pharmacokinetics, Genentech
Debra Dunlap
Pathology, Genentech
Sha Klabunde
Translational Medicine, Genentech
Priscilla Mantik
Small Molecule Pharmaceutics, Genentech
Vishnu Mohanan
Translational Medicine, Genentech
WeiYu Lin
Jacqueline McBride
Translational Medicine, Genentech
Shraddha Sadekar
Preclinical and Translational Pharmacokinetics, Genentech
Kelly M. Storek
Infectious Diseases, Genentech
Patrick Lupardus
Structural Biology, Genentech
Zhengmao Ye
Biochemical and Cellular Pharmacology, Genentech
Heidi Ackerly Wallweber
Structural Biology, Genentech
James R. Kiefer
Structural Biology, Genentech
Min Xu
Pamela Chan
Biochemical and Cellular Pharmacology, Genentech
Karthik Nagapudi
Small Molecule Pharmaceutics, Genentech
Tangsheng Yi
James T. Koerber
Antibody Engineering, Genentech