结合
化学
连接器
有效载荷(计算)
抗体-药物偶联物
体内
药代动力学
组合化学
药物代谢
新陈代谢
生物物理学
药理学
药品
抗体
生物化学
单克隆抗体
免疫学
生物
计算机科学
网络数据包
生物技术
数学
计算机网络
数学分析
操作系统
作者
Dian Su,Katherine R. Kozak,Jack Sadowsky,Shang‐Fan Yu,Aimee Fourie-O’Donohue,Christopher A. Nelson,Richard Vandlen,Rachana Ohri,Luna Liu,Carl Ng,Jintang He,Helen Davis,Jeff Lau,Geoffrey Del Rosario,Ely Cosino,Josefa dela Cruz-Chuh,Yong Ma,Donglu Zhang,Martine Darwish,Wenwen Cai
标识
DOI:10.1021/acs.bioconjchem.7b00785
摘要
Previous investigations on antibody-drug conjugate (ADC) stability have focused on drug release by linker-deconjugation due to the relatively stable payloads such as maytansines. Recent development of ADCs has been focused on exploring technologies to produce homogeneous ADCs and new classes of payloads to expand the mechanisms of action of the delivered drugs. Certain new ADC payloads could undergo metabolism in circulation while attached to antibodies and thus affect ADC stability, pharmacokinetics, and efficacy and toxicity profiles. Herein, we investigate payload stability specifically and seek general guidelines to address payload metabolism and therefore increase the overall ADC stability. Investigation was performed on various payloads with different functionalities (e.g., PNU-159682 analog, tubulysin, cryptophycin, and taxoid) using different conjugation sites (HC-A118C, LC-K149C, and HC-A140C) on THIOMAB antibodies. We were able to reduce metabolism and inactivation of a broad range of payloads of THIOMAB antibody-drug conjugates by employing optimal conjugation sites (LC-K149C and HC-A140C). Additionally, further payload stability was achieved by optimizing the linkers. Coupling relatively stable sites with optimized linkers provided optimal stability and reduction of payloads metabolism in circulation in vivo.
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