Femtogenix, Lawes Open Innovation Hub, Rothamsted Research, West Common, Harpenden, Hertfordshire, AL5 2JQ, UK.
School of Biological Sciences, Life Sciences Building B85, University of Southampton, Southampton, Hampshire, SO17 1BJ, UK.
Commun Biol. 2022 Jul 29;5(1):741. doi: 10.1038/s42003-022-03633-0.
Antibody-Drug Conjugates (ADCs) are growing in importance for the treatment of both solid and haematological malignancies. There is a demand for new payloads with novel mechanisms of action that may offer enhanced therapeutic efficacy, especially in patients who develop resistance. We report here a class of Cyclopropabenzindole-Pyridinobenzodiazepine (CBI-PDD) DNA cross-linking payloads that simultaneously alkylate guanine (G) and adenine (A) bases in the DNA minor groove with a defined sequence selectivity. The lead payload, FGX8-46 (6), produces sequence-selective G-A cross-links and affords cytotoxicity in the low picomolar region across a panel of 11 human tumour cell lines. When conjugated to the antibody cetuximab at an average Drug-Antibody Ratio (DAR) of 2, an ADC is produced with significant antitumour activity at 1 mg/kg in a target-relevant human tumour xenograft mouse model with an unexpectedly high tolerability (i.e., no weight loss observed at doses as high as 45 mg/kg i.v., single dose).
抗体药物偶联物（ADCs）在治疗实体瘤和血液恶性肿瘤方面的重要性日益增加。人们需要具有新作用机制的新型有效载荷，这些有效载荷可能提供增强的治疗效果，尤其是在产生耐药性的患者中。我们在这里报告了一类环丙烷并苯吲哚-吡啶苯并二氮杂䓬（CBI-PDD）DNA 交联有效载荷，该有效载荷可同时在 DNA 小沟中具有特定序列选择性地烷基化鸟嘌呤（G）和腺嘌呤（A）碱基。先导有效载荷 FGX8-46（6）产生序列选择性的 G-A 交联，并在 11 个人类肿瘤细胞系的面板中以低皮摩尔区域提供细胞毒性。当以平均药物抗体比（DAR）为 2 与抗体西妥昔单抗偶联时，在靶相关的人肿瘤异种移植小鼠模型中，以 1mg/kg 的剂量产生了具有显著抗肿瘤活性的 ADC，其耐受性出乎意料地高（即，在高达 45mg/kg 的静脉内单次剂量下未观察到体重减轻）。
