连接器
化学
结合
共轭体系
有效载荷(计算)
抗体-药物偶联物
二肽
组合化学
加合物
色谱法
生物化学
单克隆抗体
肽
有机化学
聚合物
抗体
网络数据包
免疫学
数学分析
操作系统
生物
计算机科学
数学
计算机网络
作者
Brian Rago,L. Nathan Tumey,Cong Wei,Frank Barletta,Tracey Clark,Steven Hansel,Xiaogang Han
标识
DOI:10.1021/acs.bioconjchem.6b00695
摘要
As antibody-drug conjugate (ADC) design is evolving with novel payload, linker, and conjugation chemistry, the need for sensitive and precise quantitative measurement of conjugated payload to support pharmacokinetics (PK) is in high demand. Compared to ADCs containing noncleavable linkers, a strategy specific to linkers which are liable to pH, chemical reduction, or enzymatic cleavage has gained popularity in recent years. One bioanalytical approach to take advantage of this type of linker design is the development of a PK assay measuring released conjugated payload. For the ADC utilizing a dipeptide ValCit linker studied in this report, the release of payload PF-06380101 was achieved with high efficiency using a purified cathepsin B enzyme. The subsequent liquid chromatography mass spectrometry (LC/MS) quantitation leads to the PK profile of the conjugated payload. For this particular linker using a maleimide-based conjugation chemistry, one potential route of payload loss would result in an albumin adduct of the linker-payload. While this adduct's formation has been previously reported, here, for the first time, we have shown that payload from a source other than ADC contributes only up to 4% of total conjugated payload while it accounts for approximately 35% of payload lost from the ADC at 48 h after dosing to rats.
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