癌相关黏蛋白16（MUC16）异常表达以及其裁剪后产生的表面系留羧基端（MUC16-Cter）与胰腺癌（PC）和非小细胞肺癌（NSCLC）的恶性预后和致死率密切相关。迄今为止，大多数抗MUC16抗体都是针对MUC16的细胞外结构域（CA125），该结构域通常会被剪切并在循环中脱落，因此阻碍了抗体对癌细胞的接近。在本研究中，我们利用一种新型嵌合抗体ch5E6，该抗体以人IgG1的格式靶向裁剪后产生的、表面系留的致癌性MUC16羧基端（MUC16-Cter）结构域，其抗原表达与两种癌症的疾病严重程度直接相关。ch5E6与MUC16相关的致癌作用，抑制下游信号传导通路pFAK(Y397)/p-p70S6K(T389)/N-连接蛋白轴，并在PC和NSCLC的癌细胞、三维器官样结构和肿瘤异种移植模型中发挥抗增殖作用。患者肿瘤和转移样本中MUC16和N-连接蛋白之间的强烈临床相关性表明ch5E6在靶向上皮-间质转化（EMT）这种与疾病恶性相关的复杂现象方面具有潜力。我们的研究支持评估ch5E6与标准护理药物的联合治疗，在MUC16相关的恶性肿瘤的治疗结果中有望取得进展。©2023年 自然出版集团英国。

Aberrantly expressed onco-mucin 16 (MUC16) and its post-cleavage generated surface tethered carboxy-terminal (MUC16-Cter) domain are strongly associated with poor prognosis and lethality of pancreatic (PC) and non-small cell lung cancer (NSCLC). To date, most anti-MUC16 antibodies are directed towards the extracellular domain of MUC16 (CA125), which is usually cleaved and shed in the circulation hence obscuring antibody accessibility to the cancer cells. Herein, we establish the utility of targeting a post-cleavage generated, surface-tethered oncogenic MUC16 carboxy-terminal (MUC16-Cter) domain by using a novel chimeric antibody in human IgG1 format, ch5E6, whose epitope expression directly correlates with disease severity in both cancers. ch5E6 binds and interferes with MUC16-associated oncogenesis, suppresses the downstream signaling pFAK(Y397)/p-p70S6K(T389)/N-cadherin axis and exert antiproliferative effects in cancer cells, 3D organoids, and tumor xenografts of both PC and NSCLC. The robust clinical correlations observed between MUC16 and N-cadherin in patient tumors and metastatic samples imply ch5E6 potential in targeting a complex and significantly occurring phenomenon of epithelial to mesenchymal transition (EMT) associated with disease aggressiveness. Our study supports evaluating ch5E6 with standard-of-care drugs, to potentially augment treatment outcomes in malignancies inflicted with MUC16-associated poor prognosis.© 2023. Nature Publishing Group UK.