连接器
结合
化学
体内
体外
细胞毒性
肽
组合化学
抗体-药物偶联物
插层(化学)
共轭体系
药品
有效载荷(计算)
抗体
立体化学
生物化学
药理学
单克隆抗体
免疫学
生物
有机化学
聚合物
生物技术
网络数据包
数学分析
操作系统
计算机科学
数学
计算机网络
作者
Michael Petersen,Michael G. Brant,Manuel Lasalle,Vincent Fung,Andrea Hernández Rojas,Jodi Wong,Samir Das,Stuart D. Barnscher,Justin Rich,Geoffrey C. Winters
标识
DOI:10.1021/acs.jmedchem.3c00760
摘要
Synthetic analogs based on the DNA bis-intercalating natural product peptides sandramycin and quinaldopeptin were investigated as antibody drug conjugate (ADC) payloads. Synthesis, biophysical characterization, and in vitro potency of 34 new analogs are described. Conjugation of an initial drug-linker derived from a novel bis-intercalating peptide produced an ADC that was hydrophobic and prone to aggregation. Two strategies were employed to improve ADC physiochemical properties: addition of a solubilizing group in the linker and the use of an enzymatically cleavable hydrophilic mask on the payload itself. All ADCs showed potent in vitro cytotoxicity in high antigen expressing cells; however, masked ADCs were less potent than payload matched unmasked ADCs in lower antigen expressing cell lines. Two pilot in vivo studies were conducted using stochastically conjugated DAR4 anti-FRα ADCs, which showed toxicity even at low doses, and site-specific conjugated (THIOMAB) DAR2 anti-cMet ADCs that were well tolerated and highly efficacious.
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