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Anti‐EGFR antibody‐drug conjugate for triple‐negative breast cancer therapy
Engineering in Life Sciences ( IF 3.9 ) Pub Date : 2020-10-07 , DOI: 10.1002/elsc.202000027
Yingnan Si 1 , Yuanxin Xu 1 , JiaShiung Guan 2 , Kai Chen 2 , Seulhee Kim 1 , Eddy S Yang 3 , Lufang Zhou 2 , Xiaoguang Margaret Liu 1
Affiliation  

Triple‐negative breast cancers (TNBCs) are highly aggressive, metastatic and recurrent. Cytotoxic chemotherapies with limited clinical benefits and severe side effects are the standard therapeutic strategies, but, to date, there is no efficacious targeted therapy. Literature and our data showed that epidermal growth factor receptor (EGFR) is overexpressed on TNBC cell surface and is a promising oncological target. The objective of this study was to develop an antibody‐drug conjugate (ADC) to target EGFR+ TNBC and deliver high‐potency drug. First, we constructed an ADC by conjugating anti‐EGFR monoclonal antibody with mertansine which inhibits microtubule assembly via linker Sulfo‐SMCC. Second, we confirmed the TNBC‐targeting specificity of anti‐EGFR ADC by evaluating its surface binding and internalization in MDA‐MB‐468 cells and targeting to TNBC xenograft in subcutaneous mouse mode. The live‐cell and live‐animal imaging with confocal laser scanning microscopy and In Vivo Imaging System (IVIS) confirmed the TNBC‐targeting. Finally, both in vitro toxicity assay and in vivo anti‐cancer efficacy study in TNBC xenograft models showed that the constructed ADC significantly inhibited TNBC growth, and the pharmacokinetics study indicated its high circulation stability. This study indicated that the anti‐EGFR ADC has a great potential to against TNBC.

中文翻译:


用于三阴性乳腺癌治疗的抗 EGFR 抗体药物偶联物



三阴性乳腺癌(TNBC)具有高度侵袭性、转移性和复发性。临床获益有限且副作用严重的细胞毒性化疗是标准治疗策略,但迄今为止,尚无有效的靶向治疗。文献和我们的数据表明,表皮生长因子受体 (EGFR) 在 TNBC 细胞表面过度表达,是一个有前途的肿瘤靶点。本研究的目的是开发一种抗体药物偶联物 (ADC),以靶向 EGFR+ TNBC 并提供高效药物。首先,我们通过将抗 EGFR 单克隆抗体与 Mertansine 结合构建了 ADC,mertansine 通过连接子 Sulfo-SMCC 抑制微管组装。其次,我们通过评估抗 EGFR ADC 在 MDA-MB-468 细胞中的表面结合和内化以及在小鼠皮下模式下靶向 TNBC 异种移植物,证实了抗 EGFR ADC 的 TNBC 靶向特异性。使用共焦激光扫描显微镜和体内成像系统 (IVIS) 进行的活细胞和活体动物成像证实了 TNBC 靶向。最后,TNBC异种移植模型的体外毒性测定和体内抗癌功效研究表明,构建的ADC显着抑制TNBC生长,药代动力学研究表明其具有较高的循环稳定性。这项研究表明抗 EGFR ADC 具有对抗 TNBC 的巨大潜力。
更新日期:2020-10-07
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