Preparation and characterization of antibody-drug conjugates acting on HER2-positive cancer cells.
Preparation and characterization of antibody-drug conjugates acting on HER2-positive cancer cells.
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DOI：
10.1371/journal.pone.0239813
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发表时间：
2020
期刊：
影响因子：
3.7
通讯作者：
Wang AH
中科院分区：
文献类型：
--
作者：
Chiang ZC;Chiu YK;Lee CC;Hsu NS;Tsou YL;Chen HS;Hsu HR;Yang TJ;Yang AS;Wang AH
通过使用与能够细胞内化的抗HER 2抗体H32连接的不同接头和药物开发了两种抗体-药物缀合物（ADC）系统，不可裂解的H32-DM 1和可裂解的H32-VCMMAE。活化的官能团，包括N-羟基琥珀酰亚胺基（NHS）酯和马来酰亚胺，用于制备ADC。通过质谱、疏水色谱、聚丙烯酰胺凝胶电泳和体外细胞分析对ADC进行分析和优化。几种H32-VCMMAE ADC被建立为具有更高的DAR和更高的合成产率而不损害效力。H32-DM 1的抗癌功效是Kadcyla®的2至8倍。H32-VCMMAE的效力又优于H32-DM 1。这些ADC针对N87、SK-BR-3和BT474细胞的抗癌功效按以下顺序：H32-VCMMAE系列> H32-DM 1系列> Kadcyla®。发现H32-VCMMAE的最佳DAR为6.6，具有期望的属性，包括良好的细胞渗透性、癌细胞中的可释放有效负载和高效力。我们的结果证明了H32-VCMMAE作为良好ADC候选物的潜力。
Two systems of antibody-drug conjugates (ADCs), noncleavable H32-DM1 and cleavable H32-VCMMAE, were developed by using different linkers and drugs attached to the anti-HER2 antibody H32, which is capable of cell internalization. Activated functional groups, including an N-hydroxysuccinimidyl (NHS) ester and a maleimide, were utilized to make the ADCs. Mass spectrometry, hydrophobic interaction chromatography, polyacrylamide gel electrophoresis, and in vitro cell assays were performed to analyze and optimize the ADCs. Several H32-VCMMAE ADCs were established with higher DARs and greater synthetic yields without compromising potency. The anticancer efficacy of H32-DM1 was 2- to 8-fold greater than that of Kadcyla®. The efficacy of H32-VCMMAE was in turn better than that of H32-DM1. The anticancer efficacy of these ADCs against N87, SK-BR-3 and BT474 cells was in the following order: H32-VCMMAE series > H32-DM1 series > Kadcyla®. The optimal DAR for H32-VCMMAE was found to be 6.6, with desirable attributes including good cell penetration, a releasable payload in cancer cells, and high potency. Our results demonstrated the potential of H32-VCMMAE as a good ADC candidate.
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影响因子：
4.6
作者：
Chen HS;Hou SC;Jian JW;Goh KS;Shen ST;Lee YC;You JJ;Peng HP;Kuo WC;Chen ST;Peng MC;Wang AH;Yu CM;Chen IC;Tung CP;Chen TH;Ping Chiu K;Ma C;Yuan Wu C;Lin SW;Yang AS
通讯作者：
Yang AS
影响因子：
56.9
作者：
COUSSENS, L;YANGFENG, TL;ULLRICH, A
通讯作者：
ULLRICH, A
影响因子：
46.9
作者：
Reichert, JM;Rosensweig, CJ;Dewitz, MC
通讯作者：
Dewitz, MC
DOI：
10.1016/j.ijgo.2008.04.008
发表时间：
2008-08-01
影响因子：
3.8
作者：
Santin, Alessandro D.;Bellone, Stefania;Pecorelli, Sergio
通讯作者：
Pecorelli, Sergio
影响因子：
4.6
作者：
Hou, Shin-Chen;Chen, Hong-Sen;Yang, An-Suei
通讯作者：
Yang, An-Suei