Spirogen, QMB Innovation Centre, 42 New Road, London, E1 2AX, United Kingdom.
AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA.
Eur J Med Chem. 2019 Oct 1;179:591-607. doi: 10.1016/j.ejmech.2019.06.044. Epub 2019 Jun 18.
Antibody-drug conjugates (ADCs) containing pyrrolobenzodiazepine (PBD) dimers are currently being evaluated in human oncology clinical trials with encouraging results. To further improve the therapeutic window, next-generation PBD drug-linker design has focused on the inclusion of additional tumor-selective triggers and use of lower-potency PBDs. β-Glucuronidase is a well-known target for discovery prodrugs due to increased presence in tumor cells and microenvironment. In this study, a β-glucuronidase cleavable cap was investigated at the PBD N10-position and compared with corresponding free imine ADCs. SG3600 (glucuronide) ADCs showed in vitro and in vivo efficacy/tolerability comparable to SG3400 (imine) ADCs, and good 50% inhibitory concentration differentials were observed in vitro between control non-antigen-targeted ADCs and targeted ADCs. Dependence on β-glucuronidase for SG3600 activity was demonstrated through CRISPRCas9 knockdown studies and addition of exogenous β-glucuronidase. SG3600 showed better serum stability, improved conjugation efficiency and was able to reach high drug-to-antibody ratio without aggregation.
抗体药物偶联物 (ADC) 中含有吡咯并苯并二氮杂 (PBD) 二聚体，目前正在进行人类肿瘤学临床试验，结果令人鼓舞。为了进一步扩大治疗窗口，新一代 PBD 药物连接子设计侧重于纳入额外的肿瘤选择性触发因素，并使用低效力的 PBD。β-葡萄糖醛酸酶由于在肿瘤细胞和微环境中存在增加，是发现前药的众所周知的靶标。在这项研究中，研究了 PBD N10 位的 β-葡萄糖醛酸酶可切割帽，并将其与相应的游离亚胺 ADC 进行了比较。SG3600（葡萄糖醛酸）ADC 在体外和体内显示出与 SG3400（亚胺）ADC 相当的疗效/耐受性，并且在体外观察到对照非抗原靶向 ADC 和靶向 ADC 之间的良好 50%抑制浓度差异。通过 CRISPRCas9 敲低研究和添加外源性β-葡萄糖醛酸酶证明了 SG3600 活性对β-葡萄糖醛酸酶的依赖性。SG3600 表现出更好的血清稳定性，提高了缀合效率，并且能够达到高药物抗体比而不聚集。
