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http://ir.nhri.org.tw/handle/3990099045/15976
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| Title: | Development of a humanized antibody targeting extracellular HSP90alpha to suppress endothelial-mesenchymal transition-enhanced tumor growth of pancreatic adenocarcinoma cells |
| Other Titles: | Development of a humanized antibody targeting extracellular HSP90α to suppress endothelial-mesenchymal transition-enhanced tumor growth of pancreatic adenocarcinoma cells |
| Authors: | 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 |
| Contributors: | National Institute of Cancer Research;Institute of Biotechnology and Pharmaceutical Research |
| Abstract: | 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. |
| Date: | 2024-07-04 |
| Relation: | 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 |
| Appears in Collections: | [黃智興] 期刊論文
[徐祖安] 期刊論文
[葉燈光] 期刊論文
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| ISI001270398000001.pdf | | 7587Kb | Adobe PDF | 39 | View/Open |
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