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Evaluation of an antibody-PNA conjugate as a clearing agent for antibody-based PNA-mediated radionuclide pretargeting
Scientific Reports ( IF 4.6 ) Pub Date : 2020-11-27 , DOI: 10.1038/s41598-020-77523-y
Anders Myrhammar , Anzhelika Vorobyeva , Kristina Westerlund , Shuichiro Yoneoka , Anna Orlova , Takehiko Tsukahara , Vladimir Tolmachev , Amelie Eriksson Karlström , Mohamed Altai

Radionuclide molecular imaging of cancer-specific targets is a promising method to identify patients for targeted antibody therapy. Radiolabeled full-length antibodies however suffer from slow clearance, resulting in high background radiation. To overcome this problem, a pretargeting system based on complementary peptide nucleic acid (PNA) probes has been investigated. The pretargeting relies on sequential injections of primary, PNA-tagged antibody and secondary, radiolabeled PNA probe, which are separated in time, to allow for clearance of non-bound primary agent. We now suggest to include a clearing agent (CA), designed for removal of primary tumor-targeting agent from the blood. The CA is based on the antibody cetuximab, which was conjugated to PNA and lactosaminated by reductive amination to improve hepatic clearance. The CA was evaluated in combination with PNA-labelled trastuzumab, T-ZHP1, for radionuclide HER2 pretargeting. Biodistribution studies in normal mice demonstrated that the CA cleared ca. 7 times more rapidly from blood than unmodified cetuximab. Injection of the CA 6 h post injection of the radiolabeled primary agent [131I]I-T-ZHP1 gave a moderate reduction of the radioactivity concentration in the blood after 1 h from 8.5 ± 1.8 to 6.0 ± 0.4%ID/g. These proof-of-principle results could guide future development of a more efficient CA.



中文翻译:

评估抗体-PNA偶联物作为基于抗体的PNA介导的放射性核素预靶向的清除剂

癌症特异性靶标的放射性核素分子成像是一种有前途的方法,可用于鉴定靶向抗体治疗的患者。然而,放射性标记的全长抗体的清除速度较慢,导致本底辐射较高。为了克服这个问题,已经研究了基于互补肽核酸(PNA)探针的预靶向系统。预先靶向依赖于顺序注射的,经过PNA标签的一级抗体和放射性标记的PNA二级探针,它们在时间上是分开的,以清除未结合的一级试剂。我们现在建议包括一种清除剂(CA),其设计用于从血液中去除原发性肿瘤靶向剂。CA基于西妥昔单抗抗体,该抗体与PNA偶联,并通过还原胺化进行乳化,以改善肝清除率。HP1,用于放射性核素HER2预靶向。在正常小鼠中进行的生物分布研究表明,CA清除了ca。与未经修饰的西妥昔单抗相比,血液抽取速度快7倍。注射放射性标记的主要药物[ 131 I] IT- ZHP1后6小时注射CA ,使1小时后血液中的放射性浓度从8.5±1.8%ID / g适度降低。这些原理验证的结果可以指导将来更高效的CA的发展。

更新日期:2020-11-27
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