连接器
结合
布仑妥昔单抗维多汀
体内
化学
PEG比率
聚乙二醇化
药理学
葡萄糖醛酸
药代动力学
抗体-药物偶联物
组合化学
生物化学
单克隆抗体
抗体
癌症研究
医学
免疫学
代谢物
聚乙二醇
生物
财务
肿瘤细胞
经济
生物技术
数学分析
操作系统
CD30
计算机科学
数学
作者
Patrick Burke,Joseph Z. Hamilton,Scott C. Jeffrey,Joshua H. Hunter,Svetlana O. Doronina,Nicole M. Okeley,Jamie B. Miyamoto,Martha E. Anderson,Ivan J. Stone,Michelle Ulrich,Jessica K. Simmons,Erica E. McKinney,Peter D. Senter,Robert P. Lyon
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2017-01-01
卷期号:16 (1): 116-123
被引量:102
标识
DOI:10.1158/1535-7163.mct-16-0343
摘要
Abstract The emergence of antibody–drug conjugates (ADC), such as brentuximab vedotin and ado-trastuzumab emtansine, has led to increased efforts to identify new payloads and develop improved drug-linker technologies. Most antibody payloads impart significant hydrophobicity to the ADC, resulting in accelerated plasma clearance and suboptimal in vivo activity, particularly for conjugates with high drug-to-antibody ratios (DAR). We recently reported on the incorporation of a discrete PEG24 polymer as a side chain in a β-glucuronidase-cleavable monomethylauristatin E (MMAE) linker to provide homogeneous DAR 8 conjugates with decreased plasma clearance and increased antitumor activity in xenograft models relative to a non-PEGylated control. In this work, we optimized the drug-linker by minimizing the size of the PEG side chain and incorporating a self-stabilizing maleimide to prevent payload de-conjugation in vivo. Multiple PEG-glucuronide-MMAE linkers were prepared with PEG size up to 24 ethylene oxide units, and homogeneous DAR 8 ADCs were evaluated. A clear relationship was observed between PEG length and conjugate pharmacology when tested in vivo. Longer PEG chains resulted in slower clearance, with a threshold length of PEG8 beyond which clearance was not impacted. Conjugates bearing PEG of sufficient length to minimize plasma clearance provided a wider therapeutic window relative to faster clearing conjugates bearing shorter PEGs. A lead PEGylated glucuronide-MMAE linker was identified incorporating a self-stabilizing maleimide and a PEG12 side chain emerged from these efforts, enabling highly potent, homogeneous DAR 8 conjugates and is under consideration for future ADC programs. Mol Cancer Ther; 16(1); 116–23. ©2016 AACR.
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