Fully human chitinase-3 like-1 monoclonal antibody inhibits tumor growth, fibrosis, angiogenesis, and immune cell remodeling in lung, pancreatic, and colorectal cancers.

Autor: Su PC; Department of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No.1, Ta-Hsueh Road, Tainan 70101, Taiwan., Chen CY; Department of Pharmacology, College of Medicine, National Cheng Kung University, No.1, Ta-Hsueh Road, Tainan 70101, Taiwan., Yu MH; Department of Pharmacology, College of Medicine, National Cheng Kung University, No.1, Ta-Hsueh Road, Tainan 70101, Taiwan., Kuo IY; Department of Biotechnology, College of Life Science, Kaohsiung Medical University, No.100, Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan., Yang PS; Department of Pharmacology, College of Medicine, National Cheng Kung University, No.1, Ta-Hsueh Road, Tainan 70101, Taiwan., Hsu CH; AP Biosciences, Inc, No. 508, Sec. 7, Zhongxiao E. Rd, Taipei 115011, Taiwan., Hou YC; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No.138, Sheng-Li Road, Tainan 70403, Taiwan; Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No.138, Sheng-Li Road, Tainan 70403, Taiwan., Hsieh HT; AP Biosciences, Inc, No. 508, Sec. 7, Zhongxiao E. Rd, Taipei 115011, Taiwan., Chang CP; Department of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No.1, Ta-Hsueh Road, Tainan 70101, Taiwan; Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, No.1, Ta-Hsueh Road, Tainan 70101, Taiwan., Shan YS; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No.138, Sheng-Li Road, Tainan 70403, Taiwan; Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No.138, Sheng-Li Road, Tainan 70403, Taiwan. Electronic address: ysshan@mail.ncku.edu.tw., Wang YC; Department of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No.1, Ta-Hsueh Road, Tainan 70101, Taiwan; Department of Pharmacology, College of Medicine, National Cheng Kung University, No.1, Ta-Hsueh Road, Tainan 70101, Taiwan. Electronic address: ycw5798@mail.ncku.edu.tw.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Jul; Vol. 176, pp. 116825. Date of Electronic Publication: 2024 May 30.
DOI: 10.1016/j.biopha.2024.116825
Abstrakt: Considering the limited efficacy of current therapies in lung, colorectal, and pancreatic cancers, innovative combination treatments with diverse mechanisms of action are needed to improve patients' outcomes. Chitinase-3 like-1 protein (CHI3L1) emerges as a versatile factor with significant implications in various diseases, particularly cancers, fostering an immunosuppressive tumor microenvironment for cancer progression. Therefore, pre-clinical validation is imperative to fully realize its potential in cancer treatment. We developed phage display-derived fully human monoclonal CHI3L1 neutralizing antibodies (nAbs) and verified the nAbs-antigen binding affinity and specificity in lung, pancreatic and colorectal cancer cell lines. Tumor growth signals, proliferation and migration ability were all reduced by CHI3L1 nAbs in vitro. Orthotopic or subcutaneous tumor mice model and humanized mouse model were established for characterizing the anti-tumor properties of two CHI3L1 nAb leads. Importantly, CHI3L1 nAbs not only inhibited tumor growth but also mitigated fibrosis, angiogenesis, and restored immunostimulatory functions of immune cells in pancreatic, lung, and colorectal tumor mice models. Mechanistically, CHI3L1 nAbs directly suppressed the activation of pancreatic stellate cells and the transformation of macrophages into myofibroblasts, thereby attenuating fibrosis. These findings strongly support the therapeutic potential of CHI3L1 nAbs in overcoming clinical challenges, including the failure of gemcitabine in pancreatic cancer.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: