8DF1

Chi3l1 bound by antibody C59

Summary for 8DF1

• Entry DOI: 10.2210/pdb8df1/pdb
• Descriptor: Chitinase-3-like protein 1, C59 Fab Heavy chain, C59 Fab Light chain, ... (6 entities in total)
• Functional Keywords: chi3l1, fab, immunotherapeutic, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 18
• Total formula weight: 524620.76

Authors

Wrapp, D.,McLellan, J.S. (deposition date: 2022-06-21, release date: 2023-03-01, Last modification date: 2024-10-09)

Primary citation

Li, L.,Wen, Y.,Wrapp, D.,Jeong, J.,Zhao, P.,Xiong, W.,Atkins, C.L.,Shan, Z.,Hui, D.,McLellan, J.S.,Zhang, N.,Ju, C.,An, Z.
A novel humanized Chi3l1 blocking antibody attenuates acetaminophen-induced liver injury in mice.
Antib Ther, 6:1-12, 2023

PubMed Abstract: Acetaminophen (APAP) overdose is a leading cause of acute liver injury in the USA. The chitinase 3-like-1 (Chi3l1) protein contributes to APAP-induced liver injury (AILI) by promoting hepatic platelet recruitment. Here, we report the development of a Chi3l1-targeting antibody as a potential therapy for AILI. By immunizing a rabbit successively with the human and mouse Chi3l1 proteins, we isolated cross-reactive monoclonal antibodies (mAbs) from single memory B cells. One of the human and mouse Chi3l1 cross-reactive mAbs was humanized and characterized in both and biophysical and biological assays. X-ray crystallographic analysis of the lead antibody C59 in complex with the human Chi3l1 protein revealed that the kappa light contributes to majority of the antibody-antigen interaction; and that C59 binds to the 4α-5β loop and 4α-helix of Chi3l1, which is a functional epitope and hotspot for the development of Chi3l1 blocking antibodies. We humanized the C59 antibody by complementarity-determining region grafting and kappa chain framework region reverse mutations. The humanized C59 antibody exhibited similar efficacy as the parental rabbit antibody C59 in attenuating AILI . Our findings validate Chi3l1 as a potential drug target for AILI and provide proof of concept of developing Chi3l1 blocking antibody as a therapy for the treatment of AILI.

PubMed: 36683763
DOI: 10.1093/abt/tbac027

Experimental method

X-RAY DIFFRACTION (3.3 Å)