化学
美罗华
结合
连接器
抗体-药物偶联物
抗体
CD20
药理学
单克隆抗体
流式细胞术
药品
癌症研究
分子生物学
免疫学
医学
生物
数学分析
操作系统
数学
计算机科学
作者
Xinyue Hu,Linlin Wang,Yue Sun,A-Long Cui
出处
期刊:Letters in Drug Design & Discovery
[Bentham Science]
日期:2022-05-01
卷期号:19 (5): 449-458
标识
DOI:10.2174/1570180818666211013111014
摘要
Background: Rituximab represents a drug used for standard Non-Hodgkin’s B-cell lymphoma therapy; however, it displays limited clinical efficacy. Antibody-drug conjugate (ADC) is one of the potential strategies to increase the antitumor activity of an antibody, with improved cytotoxicity directly resulting from the delivery of a molecular warhead. Currently, the warhead monomethyl auristatin E (MMAE) has been widely applied in the study of ADCs, conjugated to a carbamate-based linker (MCVC- PABC). However, the hydrophobic drug-linker (MC-VC-PABC-MMAE) may lead to ADC aggregation, ultimately resulting in decreased activity. Objective: In this study, we developed a hydrophilic drug-linker MC-VC-PABQ-AE linked to rituximab. If the replacement of the tertiary amine in AE for a secondary amine in MMAE represents a characteristic modification, the change of antitumor activity of two corresponding anti-CD20 ADC is unknown, requiring further verification. Method: The structural elucidation of MC-VC-PAB-AE was displayed by high-resolution mass spectra. The average drug antibody ratio (DAR) of rituximab-VC-AE/MMAE ADCs was performed by HICHPLC. The cell cycle arrest analysis of two ADCs was detected by flow cytometry and the antitumor activity of two ADCs was evaluated in vitro against Ramos and Daudi cells. Results: The average drug antibody ratio (DAR) of two ADCs was approximately 4.0. The activities of rituximab-VC-AE could be increased in CD20 positive B-lymphoma cell lines, most notably due to the higher cell viability inhibitory rates and apoptosis rates compared to rituximab-VC-MMAE. Conclusions: A hydrophilicity linker of ADC was developed and studied. Rituximab-VC-AE may potentially be used against CD20-positive cells, and the therapeutic efficacy and safety bring about further investigations.
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