PDF(Pubmed)
Abstract：
Extracellular HSP90α (eHSP90α) is a promoter of tumor development and malignant progression. Patients with malignancies, including pancreatic ductal adenocarcinoma (PDAC), have generally shown 5~10-fold increases in serum/plasma eHSP90α levels. In this study, we developed a humanized antibody HH01 to target eHSP90α and evaluated its anticancer efficacy. HH01, with novel complementarity-determining regions, exhibits high binding affinity toward HSP90α. It recognizes HSP90α epitope sites 235AEEKEDKEEE244 and 251ESEDKPEIED260, with critical amino acid residues E237, E239, D240, K241, E253, and K255. HH01 effectively suppressed eHSP90α-induced invasive and spheroid-forming activities of colorectal cancer and PDAC cell lines by blocking eHSP90α\'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 eHSP90α 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 eHSP90α with HH01 antibody can be a promising novel strategy for PDAC therapy.
摘要：
细胞外HSP90α（eHSP90α）是肿瘤发展和恶性进展的启动子。恶性肿瘤患者，包括胰腺导管腺癌（PDAC），通常显示血清/血浆eHSP90α水平增加5~10倍。在这项研究中,我们开发了针对eHSP90α的人源化抗体HH01，并评估了其抗癌功效。HH01，具有新的互补决定区，表现出对HSP90α的高结合亲和力。它识别HSP90α表位位点235AEEKEDKEEE244和251ESEDKPEIED260，具有关键氨基酸残基E237，E239，D240，K241，E253和K255。HH01通过阻断eHSP90α与细胞表面受体CD91的连接，有效抑制eHSP90α诱导的结直肠癌和PDAC细胞系的侵袭性和球状体形成活性。在老鼠模型中，HH01有效抑制由内皮-间质转化衍生的癌症相关成纤维细胞促进的PDAC细胞移植物/异种移植物的肿瘤生长，同时还降低血清eHSP90α水平，反映了其抗癌功效。HH01还通过减少M2巨噬细胞和恢复免疫T细胞来调节肿瘤免疫。此外,HH01显示低聚集倾向，高水溶性，在小鼠血液中的半衰期>18天。对视网膜色素上皮细胞无细胞毒性，对小鼠器官无明显毒性。我们的数据表明，用HH01抗体靶向eHSP90α可能是PDAC治疗的有希望的新策略。
