双位点抗HER2药物放射性结合物作为乳腺癌疗诊联合应用。
Biparatopic anti-HER2 drug radioconjugates as breast cancer theranostics.
发表日期：2023 Apr 24
作者：
Jessica Pougoue Ketchemen, Hanan Babeker, Anjong Florence Tikum, Anand Krishnan Nambisan, Fabrice Ngoh Njotu, Emmanuel Nwangele, Humphrey Fonge
来源：
BRITISH JOURNAL OF CANCER
摘要：
HER2在25-30%的乳腺癌中过度表达。靶向受体的多个区域可以具有协同/加成的治疗效果。开发了两种特定于领域的ADC：trastuzumab-PEG6-DM1（领域IV）和pertuzumab-PEG6-DM1（领域II），并对其进行了表征和放射性标记，以获得[89Zr]Zr-trastuzumab-PEG6-DM1和[67Cu]Cu-pertuzumab-PEG6-DM1，以研究它们的体外（结合测定，内化和细胞毒性）和体内（药代动力学，生物分布和免疫PET / SPECT成像）特性。 ADC的平均药物/抗体比为3。Trastuzumab未能与[67Cu]Cu-pertuzumab-PEG6-DM1竞争结合HER2。与单个抗体或ADC相比，BT-474细胞中ADC的组合观察到了最高的抗体内化。两种ADC的组合与单个ADC或对照组相比，IC50最低。药代动力学显示具有快速分布和缓慢排泄的双相半衰期，并且[89Zr]Zr-trastuzumab-PEG6-DM1的AUC是[67Cu]Cu-pertuzumab-PEG6-DM1的5倍。[89Zr]Zr-trastuzumab-PEG6-DM1的肿瘤摄取量为51.3 ± 17.3% IA/g（BT-474），12.9 ± 2.1% IA/g（JIMT-1），类似于[67Cu]Cu-pertuzumab-PEG6-DM1。受pertuzumab预先阻断的小鼠在120小时后具有[89Zr]Zr-trastuzumab-PEG6-DM1的肿瘤摄取量为66.3 ± 33.9% IA/g（BT-474）和25.3 ± 4.9％IA/g（JIMT-1）。同时将这些生物制品用作双特异治疗制剂具有加成益处。©2023 Crown.
HER2 is overexpressed in 25-30% of breast cancer. Multiple domains targeting of a receptor can have synergistic/additive therapeutic effects.Two domain-specific ADCs trastuzumab-PEG6-DM1 (domain IV) and pertuzumab-PEG6-DM1 (domain II) were developed, characterised and radiolabeled to obtain [89Zr]Zr-trastuzumab-PEG6-DM1 and [67Cu]Cu-pertuzumab-PEG6-DM1 to study their in vitro (binding assay, internalisation and cytotoxicity) and in vivo (pharmacokinetics, biodistribution and immunoPET/SPECT imaging) characteristics.The ADCs had an average drug-to-antibody ratio of 3. Trastuzumab did not compete with [67Cu]Cu-pertuzumab-PEG6-DM1 for binding to HER2. The highest antibody internalisation was observed with the combination of ADCs in BT-474 cells compared with single antibodies or ADCs. The combination of the two ADCs had the lowest IC50 compared with treatment using the single ADCs or controls. Pharmacokinetics showed biphasic half-lives with fast distribution and slow elimination, and an AUC that was five-fold higher for [89Zr]Zr-trastuzumab-PEG6-DM1 compared with [67Cu]Cu-pertuzumab-PEG6-DM1. Tumour uptake of [89Zr]Zr-trastuzumab-PEG6-DM1 was 51.3 ± 17.3% IA/g (BT-474), and 12.9 ± 2.1% IA/g (JIMT-1) which was similarly to [67Cu]Cu-pertuzumab-PEG6-DM1. Mice pre-blocked with pertuzumab had [89Zr]Zr-trastuzumab-PEG6-DM1 tumour uptakes of 66.3 ± 33.9% IA/g (BT-474) and 25.3 ± 4.9% IA/g (JIMT-1) at 120 h p.i.Using these biologics simultaneously as biparatopic theranostic agents has additive benefits.© 2023. Crown.