尽管MYCN一直被认为是一个不可用的目标,MYCN改变在许多儿童和成人癌症中导致不良预后。新的MYCN特异性抑制剂BGA002是一种与核定位信号肽共价结合的抗基因肽核酸寡核苷酸。在本研究中,我们使用一种新的特异性酶联免疫吸附试验对小鼠单次和重复给药后BGA002的药代动力学(PK)进行了表征。血浆中的BGA002浓度显示线性PK,在测试剂量水平上剂量成比例增加,男性和女性之间以及静脉和皮下给药途径之间的暴露量相似。重复给药导致血浆中没有积累。[14C]放射性标记的BGA002单次皮下给药后7天的生物分布显示出广泛的组织和器官分布(表明有可能到达一些身体部位的原发性肿瘤和转移),肾脏中的高浓度,肝脏,脾,脾淋巴结,肾上腺,还有骨髓.值得注意的是,我们证明,在三个具有MYCN扩增的小鼠模型中重复全身给药后,BGA002集中在肿瘤中(神经母细胞瘤,横纹肌肉瘤,和小细胞肺癌),导致肿瘤重量显著降低。考虑到BGA002的可用安全性,这些数据支持BGA002在MYCN阳性肿瘤患者中的进一步评估。
Although MYCN has been considered an undruggable target, MYCN alterations confer poor prognosis in many pediatric and adult cancers. The novel MYCN-specific inhibitor BGA002 is an antigene peptide nucleic acid oligonucleotide covalently bound to a nuclear localization signal peptide. In the present study, we characterized the pharmacokinetics (PK) of BGA002 after single and repeated administration to mice using a novel specific enzyme-linked immunosorbent assay. BGA002 concentrations in plasma showed linear PK, with dose proportional increase across the tested dose levels and similar exposure between male and female and between intravenous and subcutaneous route of administration. Repeated dosing resulted in no accumulation in plasma. Biodistribution up to 7 days after single subcutaneous administration of [14C]-radiolabeled BGA002 showed broad tissues and organ distribution (suggesting a potential capability to reach primary tumor and metastasis in several body sites), with high concentrations in kidney, liver, spleen, lymph nodes, adrenals, and bone marrow. Remarkably, we demonstrated that BGA002 concentrates in tumors after repeated systemic administrations in three mouse models with MYCN amplification (neuroblastoma, rhabdomyosarcoma, and small-cell lung cancer), leading to a significant reduction in tumor weight. Taking into account the available safety profile of BGA002, these data support further evaluation of BGA002 in patients with MYCN-positive tumors.