Dahal Achyut, Schlomer Jerome, Bassel Laura, Kozlov Serguei, Barchi Joseph J
Glycoconjugate and NMR Section, Chemical Biology Laboratory, The Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Center for Advanced Preclinical Research, Frederick National Lab for Cancer Research, The Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Int J Mol Sci. 2025 Jun 24;26(13):6042. doi: 10.3390/ijms26136042.
We have previously reported on a novel monoclonal antibody (mAb) we designated F5, which was raised against a glycopeptide derived from the tandem repeat (TR) region of Mucin-4 (MUC4), a heavily O-glycosylated protein that is overexpressed in many pancreatic cancer cells. This mAb was highly specific for the MUC4 glycopeptide antigen in glycan microarrays, ELISA and SPR assays, selectively stained tissue derived from advanced-stage tumors, and bound MUC4 tumor cells in flow cytometry assays. The mAb was also unique in that it did not cross-react with other commercial anti-MUC4 mAbs that were raised in a similar but non-glycosylated TR sequence. Here we describe the selective conjugation of a novel near-infrared dye to this mAb and in vivo biodistribution of this labeled mAb to various MUC4-expressing tumors in mice. The labeled mAb were selectively distributed to both cell-derived xenograft (CDX) flank tumors and patient-derived xenograft (PDX) tumors that expressed MUC4 compared to those that were MUC4-negative. Organ distribution analysis showed high uptake in MUC4 relative to MUC4 tumors. These results suggest that mAb F5 may be used to develop MUC4-targeted, passive antibody-based immunotherapies against Pancreatic Ductal Adenocarcinomas (PDACs) which are notorious for being refractory to many chemo- and radiotherapies.
我们之前报道过一种新型单克隆抗体(mAb),我们将其命名为F5,它是针对源自粘蛋白-4(MUC4)串联重复(TR)区域的糖肽产生的,MUC4是一种高度O-糖基化的蛋白质,在许多胰腺癌细胞中过表达。在聚糖微阵列、酶联免疫吸附测定(ELISA)和表面等离子体共振(SPR)测定中,这种单克隆抗体对MUC4糖肽抗原具有高度特异性,能选择性地对晚期肿瘤组织进行染色,并在流式细胞术测定中与MUC4肿瘤细胞结合。这种单克隆抗体的独特之处还在于,它不会与其他针对类似但非糖基化TR序列产生的商业抗MUC4单克隆抗体发生交叉反应。在此,我们描述了一种新型近红外染料与这种单克隆抗体的选择性偶联,以及这种标记单克隆抗体在小鼠体内对各种表达MUC4的肿瘤的生物分布。与MUC4阴性的肿瘤相比,标记的单克隆抗体选择性地分布到表达MUC4的细胞源性异种移植(CDX)侧腹肿瘤和患者源性异种移植(PDX)肿瘤中。器官分布分析显示,相对于MUC4阴性肿瘤,MUC4阳性肿瘤对标记单克隆抗体的摄取量较高。这些结果表明,单克隆抗体F5可用于开发针对胰腺导管腺癌(PDAC)的以MUC为靶点的、基于被动抗体的免疫疗法,胰腺导管腺癌因对许多化疗和放疗具有难治性而声名狼藉。