State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
Cancer Lett. 2017 Nov 28;409:125-136. doi: 10.1016/j.canlet.2017.09.004. Epub 2017 Sep 18.
The anti-human Delta-like 4 (DLL4) monoclonal antibody MMGZ01 has a high affinity to hrDLL4 and arrests the DLL4-mediated human umbilical vein endothelial cell (HUVEC) phenotype, promotes immature vessels, and effectively reduces breast cancer cell growth in vivo. To develop a much more effective therapy, we conjugated MMGZ01 with two small-molecule cytotoxic agents, i.e., monomethyl auristatin E (MMAE) and doxorubicin (DOX), with different linkers to generate antibody-drug conjugates (ADCs), i.e., MMGZ01-vc-MMAE (named MvM03) and MMGZ01-GMBS-DOX (named MGD03), that are more potent therapeutic agents than naked antibody therapeutic agents. The produced anti-DLL4 ADCs can be effectively directed against DLL4 and internalized. Then, the release of MMAE or DOX into the cytosol can induce G2/M or G0/G1 phase growth arrest and cell death through the induction of apoptosis. In vitro, MvM03 was highly potent and selective against DLL4 cell lines. The anti-DLL4 ADCs, particularly MvM03, showed more potent anti-tumour activity than Docetaxel, which is an inhibitor of the depolymerisation of microtubules, in two xenograft breast cancer tumour models. Our findings indicate that anti-DLL4 ADCs have promising potential as an effective therapy for breast cancer.
抗人 Delta 样配体 4（DLL4）单克隆抗体 MMGZ01 与人 DLL4 具有高亲和力，可阻止 DLL4 介导的人脐静脉内皮细胞（HUVEC）表型，促进不成熟血管，并有效减少体内乳腺癌细胞的生长。为了开发更有效的治疗方法，我们将 MMGZ01 与两种小分子细胞毒性药物，即单甲基奥瑞他汀 E（MMAE）和阿霉素（DOX），通过不同的连接子偶联成抗体药物偶联物（ADC），即 MMGZ01-vc-MMAE（命名为 MvM03）和 MMGZ01-GMBS-DOX（命名为 MGD03），它们比裸抗体治疗剂更有效。产生的抗 DLL4 ADC 可以有效地靶向 DLL4 并被内化。然后，MMAE 或 DOX 释放到细胞质中可以通过诱导细胞凋亡诱导 G2/M 或 G0/G1 期生长停滞和细胞死亡。在体外，MvM03 对 DLL4 细胞系具有高度的效力和选择性。两种异种移植乳腺癌肿瘤模型表明，抗 DLL4 ADC，特别是 MvM03，比微管解聚抑制剂多西紫杉醇具有更强的抗肿瘤活性。我们的研究结果表明，抗 DLL4 ADC 具有作为乳腺癌有效治疗方法的巨大潜力。
