Alsaid Hasan, Skedzielewski Tinamarie, Rambo Mary V, Hunsinger Kristen, Hoang Bao, Fieles William, Long Edward R, Tunstead James, Vugts Danielle J, Cleveland Matthew, Clarke Neil, Matheny Christopher, Jucker Beat M
Bioimaging, Platform Technology & Science, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.
Target Sciences Target & Pathway, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.
PLoS One. 2017 Apr 27;12(4):e0176075. doi: 10.1371/journal.pone.0176075. eCollection 2017.
The purpose of this work was to use various molecular imaging techniques to non-invasively assess GSK2849330 (anti HER3 ADCC and CDC enhanced 'AccretaMab' monoclonal antibody) pharmacokinetics and pharmacodynamics in human xenograft tumor-bearing mice. Immuno-PET biodistribution imaging of radiolabeled 89Zr-GSK2849330 was assessed in mice with HER3 negative (MIA-PaCa-2) and positive (CHL-1) human xenograft tumors. Dose dependency of GSK2849330 disposition was assessed using varying doses of unlabeled GSK2849330 co-injected with 89Zr-GSK2849330. In-vivo NIRF optical imaging and ex-vivo confocal microscopy were used to assess the biodistribution of GSK2849330 and the HER3 receptor occupancy in HER3 positive xenograft tumors (BxPC3, and CHL-1). Ferumoxytol (USPIO) contrast-enhanced MRI was used to investigate the effects of GSK2849330 on tumor macrophage content in CHL-1 xenograft bearing mice. Immuno-PET imaging was used to monitor the whole body drug biodistribution and CHL-1 xenograft tumor uptake up to 144 hours post injection of 89Zr-GSK2849330. Both hepatic and tumor uptake were dose dependent and saturable. The optical imaging data in the BxPC3 xenograft tumor confirmed the tumor dose response finding in the Immuno-PET study. Confocal microscopy showed a distinguished cytoplasmic punctate staining pattern within individual CHL-1 cells. GSK2849330 inhibited tumor growth and this was associated with a significant decrease in MRI signal to noise ratio after USPIO injection and with a significant increase in tumor macrophages as confirmed by a quantitative immunohistochemistry analysis. By providing both dose response and time course data from both 89Zr and fluorescently labeled GSK2849330, complementary imaging studies were used to characterize GSK2849330 biodistribution and tumor uptake in vivo. Ferumoxytol-enhanced MRI was used to monitor aspects of the immune system response to GSK2849330. Together these approaches potentially provide clinically translatable, non-invasive techniques to support dose optimization, and assess immune activation and anti-tumor responses.
这项工作的目的是使用各种分子成像技术，以无创方式评估GSK2849330（抗HER3的增强ADCC和CDC作用的“AccretaMab”单克隆抗体）在人异种移植荷瘤小鼠体内的药代动力学和药效学。在HER3阴性（MIA-PaCa-2）和阳性（CHL-1）人异种移植肿瘤小鼠中评估了放射性标记的89Zr-GSK2849330的免疫PET生物分布成像。通过与89Zr-GSK2849330共同注射不同剂量的未标记GSK2849330，评估了GSK2849330处置的剂量依赖性。体内近红外荧光（NIRF）光学成像和体外共聚焦显微镜用于评估GSK2849330在HER3阳性异种移植肿瘤（BxPC3和CHL-1）中的生物分布以及HER3受体占有率。使用铁氧还蛋白（超顺磁性氧化铁，USPIO）增强MRI来研究GSK2849330对CHL-1异种移植荷瘤小鼠肿瘤巨噬细胞含量的影响。免疫PET成像用于监测注射89Zr-GSK2849330后长达144小时的全身药物生物分布和CHL-1异种移植肿瘤摄取情况。肝脏和肿瘤摄取均呈剂量依赖性且具有饱和性。BxPC3异种移植肿瘤中的光学成像数据证实了免疫PET研究中的肿瘤剂量反应结果。共聚焦显微镜显示单个CHL-1细胞内有明显的细胞质点状染色模式。GSK2849330抑制肿瘤生长，这与USPIO注射后MRI信噪比显著降低以及定量免疫组织化学分析证实的肿瘤巨噬细胞显著增加有关。通过提供来自89Zr和荧光标记的GSK2849330的剂量反应和时间进程数据，互补成像研究用于表征GSK2849330在体内的生物分布和肿瘤摄取情况。铁氧还蛋白增强MRI用于监测免疫系统对GSK2849330反应的各个方面。这些方法共同潜在地提供了可临床转化的无创技术，以支持剂量优化，并评估免疫激活和抗肿瘤反应。
