Roche Pharmaceutical Research and Early Development, Discovery Oncology, Roche Innovation Center Munich, Penzberg, Germany
Institute for Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany; and.
J Nucl Med. 2018 Jan;59(1):44-50. doi: 10.2967/jnumed.117.197178. Epub 2017 Aug 28.
Noninvasive imaging technologies are increasingly used in preclinical drug research for the pharmacokinetic analysis of therapeutic compounds in living animals over time. The different preclinical imaging modalities available differ intrinsically in their detection principle and thus might exhibit limitations for a specific application. Here, we systematically investigated the performance of advanced fluorescence-mediated tomography (FMT)/CT in comparison to PET/MRI for quantitative analysis of the biodistribution of different antibody formats and dependence on the required imaging label in squamous cell carcinoma xenografts. Different formats of an antibody (monoclonal antibody and the antigen binding fragments F(ab') and Fab) targeting epidermal growth factor receptor were labeled with Alexa750 or Cu-NODAGA and injected intravenously into separate cohorts of nude mice bearing subcutaneous A-431 tumors. Two and 24 h after injection, the mice were measured by FMT/CT and PET/MRI. Probe accumulation was quantitatively assessed in organs and tumors. In vivo data were compared between modalities and correlated with ex vivo fluorescence, γ-counting, and electrochemiluminescence immunoassay. Both imaging methods faithfully monitored the biodistribution and elimination routes of the compounds, and organ accumulation measured by FMT/CT and PET/MRI correlated significantly with ex vivo measurements. In addition, the accumulation in kidney, muscle, and tumor tissue correlated between FMT/CT and PET/MRI. However, the pharmacokinetics of the Alexa750-labeled antibody formats showed shorter blood half-times and higher liver uptake than the radiolabeled counterparts. FMT/CT imaging allows quantifying the biodistribution of antibodies in nude mice and provides an alternative to PET analysis in preclinical drug research. However, even for large molecules, such as monoclonal antibodies, Alexa750 labeling can change pharmacokinetics and trigger liver uptake.
非侵入性成像技术在临床前药物研究中越来越多地用于分析随时间推移在活体动物中治疗化合物的药代动力学。现有的不同临床前成像方式在检测原理上存在本质差异，因此可能在特定应用中存在局限性。在这里，我们系统地研究了高级荧光介导断层扫描（FMT）/CT 与 PET/MRI 相比在定量分析不同抗体形式的生物分布以及对鳞状细胞癌异种移植中所需成像标记物的依赖性方面的性能。针对表皮生长因子受体的抗体的不同形式（单克隆抗体和抗原结合片段 F(ab')和 Fab）用 Alexa750 或 Cu-NODAGA 标记，并分别静脉注射到携带皮下 A-431 肿瘤的裸鼠中。在注射后 2 小时和 24 小时，用 FMT/CT 和 PET/MRI 对小鼠进行测量。在器官和肿瘤中定量评估探针的积累。在模态之间比较体内数据，并与离体荧光、γ 计数和电化学发光免疫分析相关。两种成像方法都忠实地监测了化合物的生物分布和消除途径，FMT/CT 和 PET/MRI 测量的器官积累与离体测量显著相关。此外，FMT/CT 和 PET/MRI 之间的相关性也表明，肾脏、肌肉和肿瘤组织的积累。然而，与放射性标记的抗体形式相比，Alexa750 标记的抗体形式的药代动力学显示较短的血液半衰期和更高的肝脏摄取。FMT/CT 成像可定量分析裸鼠中抗体的生物分布，并为临床前药物研究中的 PET 分析提供替代方法。然而，即使对于像单克隆抗体这样的大分子量分子，Alexa750 标记也可以改变药代动力学并引发肝脏摄取。
