Preparation and anti-cancer evaluation of promiximab-MMAE, an anti-CD56 antibody drug conjugate, in small cell lung cancer cell line xenograft models
Preparation and anti-cancer evaluation of promiximab-MMAE, an anti-CD56 antibody drug conjugate, in small cell lung cancer cell line xenograft models
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抗CD56抗体药物偶联物promiximab-MMAE的制备及在小细胞肺癌细胞系异种移植模型中的抗癌评价
DOI：
10.1080/1061186x.2018.1450413
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发表时间：
2018-01-01
影响因子：
4.5
通讯作者：
Yang, Jinliang
中科院分区：
文献类型：
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作者：
Yu, Lin;Yao, Yuqin;Yang, Jinliang
摘要抗体-药物偶联物（Antibody-drug conjugates, adc）作为肿瘤靶向药物已成功应用于临床。本研究将微管抑制剂MMAE与Promiximab偶联制备抗神经细胞粘附分子CD56抗体-单甲基耳抑素E （MMAE）偶联物，命名为Promiximab-MMAE。液相色谱-质谱/质谱（LC-MS/MS）分析Promiximab-MMAE的平均药抗比（DAR）为3.13。通过流式细胞术和生物层干涉分析检测，与MMAE偶联后的Promiximab-MMAE的靶向能力和亲和动力学与Promiximab相似。Promiximab-MMAE对cd56阳性细胞株（NCI-H524、NCI-H526和NCI-H69）有较好的体外抑制作用，半数最大抑制浓度（IC50）分别为19.24、5.23和0.32 nmol/L。体内给药Promiximab-MMAE，剂量为10 mg/kg / 3 d，共3次。结果表明，NCI-H69和NCI-H526移植小鼠模型到52天和56天肿瘤均未复发。此外，经Promiximab-MMAE治疗后，体重和主要器官（肝、脾、心、肺、肾）的组织病理学无明显变化。综上所述，Promiximab-MMAE是治疗CD56阳性小细胞肺癌的潜在候选药物。
Abstract Antibody-drug conjugates (ADCs) have been successfully applied clinically as target drugs for cancer. In this study, anti-neural cell adhesion molecule also called CD56 antibody-monomethyl auristatin E (MMAE) conjugate named Promiximab-MMAE was prepared by conjugation of microtubule inhibitor MMAE with Promiximab. The average drug-to-antibody ratio (DAR) of Promiximab-MMAE was 3.13 as analysed by liquid chromatography–mass spectrometry/ mass spectrometry (LC-MS/MS). The targeting capacity and affinity kinetics of Promiximab-MMAE were similar to that of Promiximab after being conjugated with MMAE as tested by flow cytometry and biolayer interferometry analysis. Promiximab-MMAE showed effective anti-proliferation on CD56-positive cell lines (NCI-H524, NCI-H526, and NCI-H69), with the half maximal inhibitory concentration (IC50) values of 19.24, 5.23, and 0.32 nmol/L in vitro, respectively. Promiximab-MMAE of 10 mg/kg every three days with a total of three times was administered in vivo. Results showed that the tumour regression was not recrudesced in NCI-H69 and NCI-H526 xenograft mice models till 52 and 56 days. Moreover, body weight and histopathology of the major organs (liver, spleen, heart, lung, and kidney) showed no significant changes after treatment with Promiximab-MMAE. In conclusion, Promiximab-MMAE is a potential candidate for the treatment of CD56 positive small cell lung cancer.