Department of Biomedical Engineering, Worcester Polytechnic Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Cancer Res. 2011 Mar 15;71(6):2230-9. doi: 10.1158/0008-5472.CAN-10-1139. Epub 2011 Jan 18.
Epidermal growth factor receptor (EGFR) imaging in brain tumors is essential to visualize overexpression of EGFRvIII variants as a signature of highly aggressive gliomas and to identify patients that would benefit from anti-EGFR therapy. Seeking imaging improvements, we tested a novel pretargeting approach that relies on initial administration of enzyme-linked anti-EGFR monoclonal antibodies (mAb; EMD72000) followed by administration of a low-molecular-weight paramagnetic molecule (diTyr-GdDTPA) retained at the site of EGFR mAb accumulation. We hypothesized that diTyr-GdDTPA would become enzyme activated and retained on cells due to binding to tissue proteins. In support of this hypothesis, mAb-enzyme conjugates reacted with both membrane-isolated wild-type (wt) EGFR and EGFRvIII, but they bound primarily to EGFRvIII-expressing cells and not to EGFRwt-expressing cells. In vivo analysis of magnetic resonance (MR) tumor signal revealed differences in MR signal decay following diTyr-GdDTPA substrate administration. These differences were significant in that they suggested differences in substrate elimination from the tissue which relied on the specificity of the initial mAb binding: a biexponential signal decay was observed in tumors only upon preinjection with EGFR-targeted conjugates. Endpoint MRI in this setting revealed detailed images of tumors which correlated with immunohistochemical detection of EGFR expression. Together, our findings suggest an improved method to identify EGFRvIII-expressing gliomas in vivo that are best suited for treatment with therapeutic EGFR antibodies.
表皮生长因子受体（EGFR）在脑肿瘤成像中至关重要，可用于可视化 EGFRvIII 变体的过表达，作为高度侵袭性神经胶质瘤的特征，并识别出将从抗 EGFR 治疗中获益的患者。为了寻求成像方面的改进，我们测试了一种新的前靶向方法，该方法依赖于初始给予酶联抗 EGFR 单克隆抗体（mAb；EMD72000），然后给予低分子量顺磁分子（diTyr-GdDTPA），该分子保留在 EGFR mAb 聚集的部位。我们假设 diTyr-GdDTPA 由于与组织蛋白结合，将在细胞中被酶激活并保留。支持这一假设的是，mAb-酶缀合物与膜分离的野生型（wt）EGFR 和 EGFRvIII 均发生反应，但它们主要与表达 EGFRvIII 的细胞结合，而不与表达 EGFRwt 的细胞结合。磁共振（MR）肿瘤信号的体内分析显示，在给予 diTyr-GdDTPA 底物后，MR 信号的衰减存在差异。这些差异具有显著性，表明从组织中消除底物的差异依赖于初始 mAb 结合的特异性：仅在预先注射 EGFR 靶向缀合物后，肿瘤才观察到双指数信号衰减。在此设置中的终点 MRI 显示了与 EGFR 表达的免疫组织化学检测相关的详细肿瘤图像。总之，我们的研究结果表明，这是一种改进的方法，可以在体内识别最适合接受治疗性 EGFR 抗体治疗的 EGFRvIII 表达神经胶质瘤。
