Si Yingnan, Xu Yuanxin, Guan JiaShiung, Chen Kai, Kim Seulhee, Yang Eddy S, Zhou Lufang, Liu Xiaoguang Margaret
Department of Biomedical Engineering University of Alabama at Birmingham (UAB) Birmingham AL USA.
Department of Medicine UAB Birmingham AL USA.
Eng Life Sci. 2020 Oct 7;21(1-2):37-44. doi: 10.1002/elsc.202000027. eCollection 2021 Jan.
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.
三阴性乳腺癌（TNBC）具有高度侵袭性、转移性和复发性。临床益处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方法。文献及我们的数据表明，表皮生长因子受体（EGFR）在TNBC细胞表面过表达，是一个有前景的肿瘤学靶点。本研究的目的是开发一种靶向EGFR TNBC并递送高效药物的抗体药物偶联物（ADC）。首先，我们通过将抗EGFR单克隆抗体与通过连接子磺基琥珀酰亚胺基4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯（Sulfo-SMCC）与美登素偶联来构建一种ADC。其次，我们通过评估其在MDA-MB-468细胞中的表面结合和内化以及在皮下小鼠模型中对TNBC异种移植瘤的靶向性，来确认抗EGFR ADC的TNBC靶向特异性。共聚焦激光扫描显微镜和体内成像系统（IVIS）的活细胞和活体动物成像证实了其对TNBC的靶向性。最后，在TNBC异种移植瘤模型中的体外毒性试验和体内抗癌疗效研究均表明，构建的ADC显著抑制TNBC生长，药代动力学研究表明其具有高循环稳定性。本研究表明，抗EGFR ADC具有对抗TNBC的巨大潜力。
