The La antigen is over-expressed in lung cancer and is a selective dead cancer cell target for radioimmunotherapy using the La-specific antibody APOMAB®.
The La antigen is over-expressed in lung cancer and is a selective dead cancer cell target for radioimmunotherapy using the La-specific antibody APOMAB®.
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DOI：
10.1186/2191-219x-4-2
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发表时间：
2014-01-04
期刊：
影响因子：
3.2
通讯作者：
Brown MP
中科院分区：
文献类型：
--
作者：
Staudacher AH;Al-Ejeh F;Fraser CK;Darby JM;Roder DM;Ruszkiewicz A;Manavis J;Brown MP
狼疮相关(La)特异性鼠单抗DAB4(APOMAB®)可与死亡的癌细胞特异性结合。利用DAB4，我们检测了人肺癌样本中La的表达，以评估其作为癌症选择性治疗靶点的适用性。在小鼠Lewis肺癌(LL2)模型中，我们评估了放射性免疫治疗(RIT)的安全性和有效性，并确定了RIT与DNA损伤的顺铂为主的化疗、PARP抑制剂(PARPI)或两者结合是否改变了治疗反应。使用Oncomine在线数据库分析人肺癌标本中La基因的表达，并使用TIssueFocus癌症调查组织芯片检测La的蛋白表达。体外检测DAB4与顺铂处理的LL2细胞的结合情况。给L12荷瘤小鼠单独或联合化疗递增剂量的177Lu-DAB4，测量肿瘤生长和存活率。生物分布分析用于确定单独给药或化疗后的177Lu-DAB4或其同型对照(177Lu-Sal5)的组织摄取。PARPI(Rucaparib；AG-014699)联合化疗，分析联合治疗对肿瘤生长、肿瘤细胞DNA损伤和死亡以及瘤内DAB_4结合的影响。检测了PARPI、化疗和177Lu-DAB4三联疗法对L12荷瘤小鼠肿瘤生长和存活的影响。在肺癌手术标本中，La在mRNA和蛋白水平均有过度表达，且La mRNA过度表达提示预后不良。DAB4在体外与顺铂诱导的死亡L12细胞特异性结合。当体内递增剂量的177Lu-DAB4时，观察到抗肿瘤的剂量反应，当化疗与177Lu-DAB4联合使用时，观察到超相加反应。PARPI联合化疗比单纯化疗更有效，肿瘤细胞DNA损伤和死亡增加，瘤内DAB4结合。PARPI、化疗和177Lu-DAB4的组合耐受性良好，最大限度地延缓了肿瘤的生长。La抗原代表肺癌中死亡的癌细胞特异性靶点，而DAB4则专门针对体内的肿瘤组织，特别是在化疗后。在PARPI和化疗结合后，肿瘤对DAB4的摄取进一步增加，这产生了新的死亡的肿瘤细胞结合靶点。因此，将177Lu-DAB4与PARPI和化疗相结合产生了最大的抗肿瘤反应。因此，PARPI、化疗和RIT三联疗法可能具有广泛的临床应用价值。
The lupus-associated (La)-specific murine monoclonal antibody DAB4 (APOMAB®) specifically binds dead cancer cells. Using DAB4, we examined La expression in human lung cancer samples to assess its suitability as a cancer-selective therapeutic target. We evaluated the safety and effectiveness of radioimmunotherapy (RIT) using DAB4 radiolabeled with Lutetium-177 (177Lu) in the murine Lewis Lung (LL2) carcinoma model, and determined whether combining RIT with DNA-damaging cisplatin-based chemotherapy, a PARP inhibitor (PARPi), or both alters treatment responses. The expression of La mRNA in human lung cancer samples was analysed using the online database Oncomine, and the protein expression of La was examined using a TissueFocus Cancer Survey Tissue Microarray. The binding of DAB4 to cisplatin-treated LL2 cells was assessed in vitro. LL2 tumour-bearing mice were administered escalating doses of 177Lu-DAB4 alone or in combination with chemotherapy, and tumour growth and survival measured. Biodistribution analysis was used to determine tissue uptake of 177Lu-DAB4 or its isotype control (177Lu-Sal5), when delivered alone or after chemotherapy. PARPi (rucaparib; AG-014699) was combined with chemotherapy and the effects of combined treatment on tumour growth, tumour cell DNA damage and death, and intratumoural DAB4 binding were also analysed. The effect of the triple combination of PARPi, chemotherapy and 177Lu-DAB4 on tumour growth and survival of LL2 tumour-bearing mice was tested. La was over-expressed at both mRNA and protein levels in surgical specimens of human lung cancer and the over-expression of La mRNA conferred a poorer prognosis. DAB4 bound specifically to cisplatin-induced dead LL2 cells in vitro. An anti-tumour dose response was observed when escalating doses of 177Lu-DAB4 were delivered in vivo, with supra-additive responses observed when chemotherapy was combined with 177Lu-DAB4. Combining PARPi with chemotherapy was more effective than chemotherapy alone with increased tumour cell DNA damage and death, and intratumoural DAB4 binding. The combination of PARPi, chemotherapy and 177Lu-DAB4 was well-tolerated and maximised tumour growth delay. The La antigen represents a dead cancer cell-specific target in lung cancer, and DAB4 specifically targeted tumour tissue in vivo, particularly after chemotherapy. Tumour uptake of DAB4 increased further after the combination of PARPi and chemotherapy, which generated new dead tumour cell-binding targets. Consequently, combining 177Lu-DAB4 with PARPi and chemotherapy produced the greatest anti-tumour response. Therefore, the triple combination of PARPi, chemotherapy and RIT may have broad clinical utility.