Developmental Therapeutics Program, Department of Diagnostic Imaging, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Clin Cancer Res. 2011 Mar 15;17(6):1509-20. doi: 10.1158/1078-0432.CCR-10-1654. Epub 2010 Dec 21.
The rapid tumor targeting and pharmacokinetic properties of engineered antibodies make them potentially suitable for use in imaging strategies to predict and monitor response to targeted therapies. This study aims to evaluate C6.5 diabody (C6.5 db), a noncovalent anti-HER2 single-chain Fv dimer, as a radiotracer for predicting response to HER2-targeted therapies such as trastuzumab.
Immunodeficient mice bearing established HER2-positive tumor xenografts were injected with radioiodinated C6.5 db and imaged by PET/CT. Radiotracer biodistribution was quantified by biopsied tumor and normal tissues. Potential competition between trastuzumab and C6.5 db was examined in vitro by flow cytometry and coimmunoprecipitations.
Biodistribution analysis of mice bearing xenografts with varying HER2 density revealed that the tumor uptake of (125)I-C6.5 db correlates with HER2 tumor density. In vitro competition experiments suggest that the C6.5 db targets an epitope on HER2 that is distinct from that bound by trastuzumab. Treatment of mice affected with SK-OV-3 tumor with trastuzumab for 3 days caused a 42% (P = 0.002) decrease in tumor uptake of (125)I-C6.5 db. This is consistent with a dramatic decrease in the tumor PET signal of (124)I-C6.5 db after trastuzumab treatment. Furthermore, mice affected with BT-474 tumor showed an approximately 60% decrease (P = 0.0026) in C6.5 db uptake after 6 days of trastuzumab treatment. Immunohistochemistry of excised xenograft sections and in vitro flow cytometry revealed that the decreased C6.5 db uptake on trastuzumab treatment is not associated with HER2 downregulation.
These studies suggest that (124)I-C6.5 db-based imaging can be used to evaluate HER2 levels as a predictor of response to HER2-directed therapies.
工程抗体具有快速肿瘤靶向和药代动力学特性，使其有可能适用于成像策略，以预测和监测对靶向治疗的反应。本研究旨在评估 C6.5 二抗（C6.5 db），一种非共价抗 HER2 单链 Fv 二聚体，作为放射性示踪剂，用于预测曲妥珠单抗等 HER2 靶向治疗的反应。
用放射性碘标记的 C6.5 db 注射免疫缺陷小鼠，并用 PET/CT 进行成像。通过肿瘤和正常组织活检定量测定示踪剂的生物分布。通过流式细胞术和共免疫沉淀在体外研究曲妥珠单抗与 C6.5 db 之间的潜在竞争。
对具有不同 HER2 密度的异种移植瘤小鼠的生物分布分析表明，（125）I-C6.5 db 在肿瘤中的摄取与 HER2 肿瘤密度相关。体外竞争实验表明，C6.5 db 针对的是 HER2 上的一个表位，与曲妥珠单抗结合的表位不同。用曲妥珠单抗治疗 SK-OV-3 肿瘤 3 天的小鼠，（125）I-C6.5 db 在肿瘤中的摄取减少了 42%（P=0.002）。这与曲妥珠单抗治疗后（124）I-C6.5 db 的肿瘤 PET 信号明显下降一致。此外，BT-474 肿瘤的小鼠在曲妥珠单抗治疗 6 天后，C6.5 db 的摄取量减少了约 60%（P=0.0026）。切除的异种移植瘤标本的免疫组织化学和体外流式细胞术显示，曲妥珠单抗治疗后 C6.5 db 摄取减少与 HER2 下调无关。
这些研究表明，（124）I-C6.5 db 成像可用于评估 HER2 水平，作为对 HER2 靶向治疗反应的预测指标。
