國家衛生研究院 NHRI:Item 3990099045/15976
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    题名: Development of a humanized antibody targeting extracellular HSP90alpha to suppress endothelial-mesenchymal transition-enhanced tumor growth of pancreatic adenocarcinoma cells
    其它题名: Development of a humanized antibody targeting extracellular HSP90α to suppress endothelial-mesenchymal transition-enhanced tumor growth of pancreatic adenocarcinoma cells
    作者: Fan, CS;Hung, HC;Chen, CC;Chen, LL;Ke, YY;Yeh, TK;Huang, CT;Chang, TY;Yen, KJ;Chen, CH;Chua, KV;Hsu, JTA;Huang, TS
    贡献者: National Institute of Cancer Research;Institute of Biotechnology and Pharmaceutical Research
    摘要: Extracellular HSP90 alpha (eHSP90 alpha) is a promoter of tumor development and malignant progression. Patients with malignancies, including pancreatic ductal adenocarcinoma (PDAC), have generally shown 5 similar to 10-fold increases in serum/plasma eHSP90 alpha levels. In this study, we developed a humanized antibody HH01 to target eHSP90 alpha and evaluated its anticancer efficacy. HH01, with novel complementarity-determining regions, exhibits high binding affinity toward HSP90 alpha. It recognizes HSP90 alpha epitope sites (235)AEEKEDKEEE(244) and 251ESEDKPEIED260, with critical amino acid residues E237, E239, D240, K241, E253, and K255. HH01 effectively suppressed eHSP90 alpha-induced invasive and spheroid-forming activities of colorectal cancer and PDAC cell lines by blocking eHSP90 alpha's ligation with the cell-surface receptor CD91. In mouse models, HH01 potently inhibited the tumor growth of PDAC cell grafts/xenografts promoted by endothelial-mesenchymal transition-derived cancer-associated fibroblasts while also reducing serum eHSP90 alpha levels, reflecting its anticancer efficacy. HH01 also modulated tumor immunity by reducing M2 macrophages and reinvigorating immune T-cells. Additionally, HH01 showed low aggregation propensity, high water solubility, and a half-life time of >18 days in mouse blood. It was not cytotoxic to retinal pigmented epithelial cells and showed no obvious toxicity in mouse organs. Our data suggest that targeting eHSP90 alpha with HH01 antibody can be a promising novel strategy for PDAC therapy.
    日期: 2024-07-04
    關聯: Cells. 2024 Jul 04;13(13):Article number 1146.
    Link to: http://dx.doi.org/10.3390/cells13131146
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2073-4409&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:001270398000001
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85198344089
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