Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Neuro Oncol. 2024 Jun 3;26(6):1067-1082. doi: 10.1093/neuonc/noae025.
The aim of this study is an improved understanding of drug distribution in brain metastases. Rather than single point snapshots, we analyzed the time course and route of drug/probe elimination (clearance), focusing on the intramural periarterial drainage (IPAD) pathway.
Mice with JIMT1-BR HER2+ experimental brain metastases were injected with biocytin-TMR and either trastuzumab or human IgG. Drugs/probes circulated for 5 min to 48 h, followed by perfusion. Brain sections were stained for human IgG, vascular basement membrane proteins laminin or collagen IV, and periarterial α-SMA. A machine learning algorithm was developed to identify metastases, metastatic microenvironment, and uninvolved brain in confocally scanned brain sections. Drug/probe intensity over time and total imaged drug exposure (iAUC) were calculated for 27,249 lesions and co-immunofluorescence with IPAD-vascular matrix analyzed in 11,668 metastases.
In metastases, peak trastuzumab levels were 5-fold higher than human IgG but 4-fold less than biocytin-TMR. The elimination phase constituted 85-93% of total iAUC for all drugs/probes tested. For trastuzumab, total iAUC during uptake was similar to the small molecule drug probe biocytin-TMR, but slower trastuzumab elimination resulted in a 1.7-fold higher total iAUC. During elimination trastuzumab and IgG were preferentially enriched in the α-SMA+ periarterial vascular matrix, consistent with the IPAD clearance route; biocytin-TMR showed heterogeneous elimination pathways.
Drug/probe elimination is an important component of drug development for brain metastases. We identified a prolonged elimination pathway for systemically administered antibodies through the periarterial vascular matrix that may contribute to the sustained presence and efficacy of large antibody therapeutics.
本研究旨在深入了解脑转移瘤中的药物分布。我们分析了药物/探针的消除（清除）的时程和途径，而不是单点快照，重点关注颅内动脉周围引流（IPAD）途径。
将具有 JIMT1-BR HER2+实验性脑转移的小鼠注射生物胞素-TMR 和曲妥珠单抗或人 IgG。药物/探针循环 5 分钟至 48 小时，然后进行灌注。脑切片用抗人 IgG、血管基底膜蛋白层粘连蛋白或胶原 IV 和动脉周围 α-SMA 染色。开发了一种机器学习算法来识别共聚焦扫描脑切片中的转移瘤、转移性微环境和未受累的脑。计算了 27,249 个病变的药物/探针强度随时间的变化和总成像药物暴露（iAUC），并在 11,668 个转移瘤中对 IPAD-血管基质的共免疫荧光进行了分析。
在转移瘤中，曲妥珠单抗的峰值水平是 IgG 的 5 倍，但比生物胞素-TMR 低 4 倍。所有测试药物/探针的消除相构成总 iAUC 的 85-93%。对于曲妥珠单抗，摄取期间的总 iAUC 与小分子药物探针生物胞素-TMR 相似，但由于曲妥珠单抗的消除较慢，总 iAUC 增加了 1.7 倍。在消除过程中，曲妥珠单抗和 IgG 优先富集在动脉周围的 α-SMA+血管基质中，与 IPAD 清除途径一致；生物胞素-TMR 显示出不均匀的消除途径。
药物/探针的消除是脑转移瘤药物开发的重要组成部分。我们确定了一种通过动脉周围血管基质系统给药的抗体的延长消除途径，这可能有助于大抗体治疗药物的持续存在和疗效。
