【靶点聚焦】【靶点新势力】“网红靶点”DLL3，全方位助力肺癌治疗药物开发

Notch信号通路是高度保守的细胞间信号传导通路，涉及生长发育的多个过程，包括多能祖细胞的分化、细胞凋亡、细胞增殖及细胞边界的形成等。Delta‐like canonical Notch ligand 3 (DLL3)是Notch通路配体家族的成员，在Notch信号传导中发挥关键作用。研究发现，DLL3在小细胞肺癌(SCLC)和其他神经内分泌肿瘤中高表达，而在正常组织中很少表达，进而引起了人们对于其作为一种新的癌症治疗靶点的兴趣，越来越多的研究者在寻找靶向DLL3精准治疗肺癌的方法¹。

DLL3为一种附着在细胞表面的单次跨膜蛋白，人DLL3蛋白由619个氨基酸组成，完整结构包含1个DSL结构域、1个胞内结构域和6个表皮生长因子样结构域。与其他Notch配体不同，DLL3通常表达于高尔基体并在过表达时出现在细胞表面，且被发现不与Notch受体结合，被认为是Notch信号传导的细胞自主抑制剂^2，3。

图1. DLL3结构示意图

最新研究发现，DLL3在小细胞肺癌(small‐cell lung cancer, SCLC）和大细胞神经内分泌癌(large cell neuroendocrine carcinoma, LCNEC)细胞表面高表达。目前靶向DLL3的抗体药物偶联物ROVA-T是一种很有前景的靶向治疗药物，在SCLC和LCNEC中显示出有效的消退效果。抑制DLL3的表达可以抑制以上两种细胞生长并诱导细胞凋亡，因此DLL3被认为是新型肺癌治疗的潜在靶标。此外，DLL3被发现是ASCL1的直接下游靶标, 而ASCL1是一种与肺神经内分泌细胞发育相关的转录因子，表明DLL3与神经内分泌肿瘤发生有关，特别是在肺癌相关的神经内分泌肿瘤^4，5，6。

然而ROVA-T的开发由于与其阳性对照拓扑替康相比较短的总生存期(Overall Survival, OS）而被暂停^7，8，9。临床研究数据表明，DLL3在超过80%的小细胞肺癌中患者中高表达，且SCLC中DLL3的高表达与患者的生存期呈现负相关，即DLL3表达量越高，患者的生存期越低¹⁰。

该技术使用抗体光敏剂偶联物，使用近红外光照射并特异性损伤癌细胞。用ROVA-IR700 孵育的细胞，其中ROVA-T抗体偶联IR700光敏剂在近红外光照射下明显溶解。此外，观察到用采用 ROVA-IR700 治疗的小鼠的异种移植物有显著缩小¹³。

双特异性T细胞接合剂(bispecific T‐cell engager，BiTE）是一种新型免疫治疗方法，可重定向患者的T细胞以杀死肿瘤细胞。由安进开发的AMG 757经过优化后延长了BiTE 分子半衰期，可激活T细胞靶向表达DLL3的肿瘤。经验证，AMG 757在体外对SCLC细胞系有效；在小鼠模型中，AMG 757通过活化T细胞使得患者来源的异种移植物和原位SCLC 肿瘤中显着消退，表明AMG 757有望成为靶向DLL3的新型SCLC免疫治疗药物。针对 SCLC患者的AMG 757临床I期研究(NCT03319940)正在进行中¹⁴。

参考文献：

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