Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD 21287, United States; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, United States.
Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD 21287, United States.
Biochem Biophys Res Commun. 2014 Jan 10;443(2):635-40. doi: 10.1016/j.bbrc.2013.12.014. Epub 2013 Dec 11.
The receptor tyrosine kinase Axl is overexpressed in and leads to patient morbidity and mortality in a variety of cancers. Axl-Gas6 interactions are critical for tumor growth, angiogenesis and metastasis. The goal of this study was to investigate the feasibility of imaging graded levels of Axl expression in tumors using a radiolabeled antibody. We radiolabeled anti-human Axl (Axl mAb) and control IgG1 antibodies with (125)I with high specific radioactivity and radiochemical purity, resulting in an immunoreactive fraction suitable for in vivo studies. Radiolabeled antibodies were investigated in severe combined immunodeficient mice harboring subcutaneous CFPAC (Axl(high)) and Panc1 (Axl(low)) pancreatic cancer xenografts by ex vivo biodistribution and imaging. Based on these results, the specificity of [(125)I]Axl mAb was also validated in mice harboring orthotopic Panc1 or CFPAC tumors and in mice harboring subcutaneous 22Rv1 (Axl(low)) or DU145 (Axl(high)) prostate tumors by ex vivo biodistribution and imaging studies at 72h post-injection of the antibody. Both imaging and biodistribution studies demonstrated specific and persistent accumulation of [(125)I]Axl mAb in Axl(high) (CFPAC and DU145) expression tumors compared to the Axl(low) (Panc1 and 22Rv1) expression tumors. Axl expression in these tumors was further confirmed by immunohistochemical studies. No difference in the uptake of radioactivity was observed between the control [(125)I]IgG1 antibody in the Axl(high) and Axl(low) expression tumors. These data demonstrate the feasibility of imaging Axl expression in pancreatic and prostate tumor xenografts.
受体酪氨酸激酶 Axl 在多种癌症中过度表达，并导致患者的发病率和死亡率。Axl-Gas6 相互作用对于肿瘤生长、血管生成和转移至关重要。本研究的目的是研究使用放射性标记抗体对肿瘤中 Axl 表达进行分级成像的可行性。我们用高比活度和高放射化学纯度的 (125)I 对抗人 Axl（Axl mAb）和对照 IgG1 抗体进行放射性标记，得到适合体内研究的免疫反应性部分。通过体外生物分布和成像研究，在皮下携带 CFPAC（Axl(high)）和 Panc1（Axl(low)）胰腺癌细胞异种移植的严重联合免疫缺陷小鼠中研究了放射性标记的抗体。基于这些结果，还通过在携带原位 Panc1 或 CFPAC 肿瘤的小鼠和携带皮下 22Rv1（Axl(low)）或 DU145（Axl(high)）前列腺肿瘤的小鼠中进行的体外生物分布和成像研究，验证了 [(125)I]Axl mAb 的特异性。在注射抗体后 72 小时，成像和生物分布研究均表明，与 Axl(low)（Panc1 和 22Rv1）表达肿瘤相比，[(125)I]Axl mAb 在 Axl(high)（CFPAC 和 DU145）表达肿瘤中具有特异性和持续的积累。免疫组织化学研究进一步证实了这些肿瘤中的 Axl 表达。在 Axl(high)和 Axl(low)表达肿瘤中，[(125)I]IgG1 对照抗体的放射性摄取没有差异。这些数据表明，在胰腺和前列腺肿瘤异种移植中成像 Axl 表达是可行的。
