Preclinical Evaluation of the Toxicological Effects of a Novel Constrained Ethyl Modified Antisense Compound Targeting Signal Transducer and Activator of Transcription 3 in Mice and Cynomolgus Monkeys
Preclinical Evaluation of the Toxicological Effects of a Novel Constrained Ethyl Modified Antisense Compound Targeting Signal Transducer and Activator of Transcription 3 in Mice and Cynomolgus Monkeys
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DOI：
10.1089/nat.2013.0422
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发表时间：
2013-06-01
影响因子：
4
通讯作者：
Henry, Scott P.
中科院分区：
文献类型：
--
作者：
Burel, Sebastien A.;Han, So-Ri;Henry, Scott P.
ISIS 481464是一种限制性乙基（cEt）修饰的硫代磷酸酯反义寡核苷酸（阿索），靶向在小鼠和猴中研究的信号转导子和转录激活子3（STAT 3），以支持肿瘤学临床试验。在小鼠和食蟹猴中进行了6周毒理学研究（分别高达70和30 mg/kg/周）。在猴中观察到STAT 3蛋白减少至对照的90%。就药代动力学特性而言，食蟹猴被认为是与人类最相关的种属，但小鼠对寡核苷酸的潜在促炎和肝脏效应的相对敏感性是有用的。在猴中，以高达30 mg/kg/周的剂量给药6周，对器官功能无影响。在肾脏内观察到极轻微至轻微的近端肾小管上皮细胞变性和再生，对肾功能无影响，并且在停药期结束时显示可逆性。此外，仅在较高剂量静脉给药时观察到轻度和一过性活化部分凝血活酶时间升高以及补体Bb轻度增加。在小鼠中，70 mg/ kg/周剂量组的变化包括脾脏重量相对于对照组增加1.4倍，丙氨酸氨基转移酶和天冬氨酸氨基转移酶相对于对照组增加1.8倍，白细胞介素-10相对于对照组增加3.7倍，单核细胞趋化蛋白-1相对于对照组增加1.9倍。在20 mg/kg/周或更低剂量下，在小鼠中未观察到显著的临床病理学或组织病理学变化。ISIS 481464的毒性特征与用含有2 '-O-甲氧基乙基核糖修饰而不是cEt的硫代磷酸酯ASO观察到的效果一致。
ISIS 481464 is a constrained ethyl (cEt) modified phosphorothioate antisense oligonucleotide (ASO) targeting signal transducer and activator of transcription 3 (STAT3) studied in mice and monkey to support oncology clinical trials. Six-week toxicology studies were performed in mice and cynomolgus monkey (up to 70 and 30 mg/kg/week respectively). Reduction in STAT3 protein up to 90% of control was observed in monkey. Cynomolgus monkey was considered the most relevant species to human with respect to pharmacokinetic properties, but mice are useful in their relative sensitivity to the potential proinflammatory and hepatic effects of oligonucleotides. In monkeys, there was no impact on organ function at doses up to 30mg/kg/week for 6 weeks. Minimal to slight proximal tubular epithelial cell degeneration and regeneration within the kidney was observed, which had no impact on renal function and showed reversibility at the end of the treatment-free period. Additionally, mild and transient activated partial thromboplastin time elevations and mild increases in complement Bb were observed at the higher doses by intravenous dosing only. In mice, the alterations at 70 mg/ kg/week included spleen weight increase up to 1.4-fold relative to control, increases in alanine aminotransferase and aspartate aminotransferase up to 1.8-fold over control, interleukin-10 increases up to 3.7-fold, and monocyte chemoattractant protein-1 increase up to 1.9-fold over control. No significant clinical pathology or histopathology changes were seen in mice at 20mg/kg/week or less. The toxicity profile of ISIS 481464 is consistent with effects observed with phosphorothioate ASOs containing 2'-O-methoxyethylribose modifications instead of cEt.