CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Syndecan-1-targeted therapeutic antibody impairs macropinocytosis and elicits antitumor immunity in pancreatic cancer.
Syndecan-1-targeted therapeutic antibody impairs macropinocytosis and elicits antitumor immunity in pancreatic cancer.
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胰腺导管腺癌（PDAC）仍然是最致命的恶性肿瘤之一，5年生存率仅为13%。尽管靶向PDAC关键驱动因素——致癌性KRAS突变的小分子药物的开发和早期临床使用已显示出前景，但对这些靶向治疗的耐药性仍然是一个重大挑战。我们最近发现Syndecan-1（SDC1），一种高表达的硫酸乙酰肝素蛋白聚糖，是促进营养 salvage 和肿瘤生长的关键KRAS效应蛋白。在此，我们报道了一种人特异性单克隆抗体（抗SDC1 mAb）的开发，该抗体在体外抑制PDAC细胞增殖，并在体内抑制PDAC肿瘤生长。在机制上，抗SDC1 mAb阻断巨胞饮作用并诱导抗体依赖性细胞毒性（ADCC）。在体内，抗SDC1 mAb与标准化疗、KRAS ∗抑制剂和免疫疗法协同作用，导致肿瘤消退和接近完全缓解。这些发现突显了抗SDC1 mAb作为PDAC以及潜在其他KRAS ∗和SDC1驱动肿瘤的有前景的治疗策略。
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with a 5-year survival rate of just 13%. While the development and early clinical use of small molecules targeting oncogenic KRAS mutations, key drivers of PDAC, have shown promise, resistance to these targeted therapies remains a significant challenge.
We recently identified Syndecan-1 (SDC1), a highly expressed heparan sulfate proteoglycan, as a critical KRAS effector protein that promotes nutrient salvage and tumor growth.
Here, we report the development of a human-specific monoclonal antibody (anti-SDC1 mAb) that inhibits PDAC cell proliferation in vitro and suppresses PDAC tumor growth in vivo.
Mechanistically, the anti-SDC1 mAb blocks macropinocytosis and induces antibody-dependent cellular cytotoxicity (ADCC). In vivo, anti-SDC1 mAb synergizes with standard chemotherapy, KRAS ∗ inhibitors, and immunotherapies, resulting in tumor regression and near-complete response.
These findings highlight the anti-SDC1 mAb as a promising therapeutic strategy for PDAC and potentially other KRAS ∗ and SDC1-driven tumors.
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