8df1
From Proteopedia
Chi3l1 bound by antibody C59
Structural highlights
DiseaseCH3L1_HUMAN A genetic variation in CHI3L1 is associated with susceptibility to asthma-related traits type 7 (ASRT7) [MIM:611960. Asthma-related traits include clinical symptoms of asthma, such as coughing, wheezing and dyspnea, bronchial hyperresponsiveness (BHR) as assessed by methacholine challenge test, serum IgE levels, atopy, and atopic dermatitis. FunctionCH3L1_HUMAN Carbohydrate-binding lectin with a preference for chitin. May play a role in defense against pathogens, or in tissue remodeling. May play an important role in the capacity of cells to respond to and cope with changes in their environment.[1] Publication Abstract from PubMedAcetaminophen (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 in vitro and in vivo 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 4alpha-5beta loop and 4alpha-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 in vivo. 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. A novel humanized Chi3l1 blocking antibody attenuates acetaminophen-induced liver injury in mice.,Li L, Wen Y, Wrapp D, Jeong J, Zhao P, Xiong W, Atkins CL, Shan Z, Hui D, McLellan JS, Zhang N, Ju C, An Z Antib Ther. 2022 Nov 7;6(1):1-12. doi: 10.1093/abt/tbac027. eCollection 2023 Jan. PMID:36683763[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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