HER1-targeted 86Y-panitumumab possesses superior targeting characteristics than 86Y-cetuximab for PET imaging of human malignant mesothelioma tumors xenografts.
HER1-targeted 86Y-panitumumab possesses superior targeting characteristics than 86Y-cetuximab for PET imaging of human malignant mesothelioma tumors xenografts.
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DOI：
10.1371/journal.pone.0018198
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发表时间：
2011-03-25
期刊：
影响因子：
3.7
通讯作者：
Brechbiel MW
中科院分区：
文献类型：
--
作者：
Nayak TK;Garmestani K;Milenic DE;Baidoo KE;Brechbiel MW
恶性间皮瘤(MM)是一种罕见的癌症，通常与既往接触石棉等纤维矿物有关。石棉暴露增加了临床前模型中HER1的活性和表达。此外，在大多数MM病例中观察到HER1的过度表达。在这项研究中，评估了HER1靶向嵌合的IgG1，西妥昔单抗和人的IgG2，Panitumab，86Y标记的PET成像在体内非侵入性检测MM的应用，并选择了用于放射免疫治疗(RIT)的候选抗体。西妥昔单抗和帕尼妥单抗分别与CHX-A‘-DTPA偶联，然后用~(86)Y标记，制备了西妥昔单抗和帕尼妥单抗的放射免疫结合物(RIC)。流式细胞仪检测NCI-H2 6、NCI-H2052、NCI-H2452和MSTO-211H间皮瘤细胞HER1的表达。在荷瘤裸鼠体内进行生物分布、药代动力学分析和PET成像。体内研究表明，HER1肿瘤对两种RIC的摄取都很高。在联合注射过量mAb(0.1 mg)的小鼠中观察到肿瘤摄取显著减少，表明肿瘤中的摄取是受体特异性的。RICS的体内特性有显著差异。86Y-西妥昔单抗的血药清除率Tüα(0.9~1.1h)明显快于86Y-Panitumab(2.6~3.1h)。此外，根据PET肿瘤与背景比率的差异，86Y-panitumab的肿瘤曲线下面积(AUC)与肝脏AUC的比率比86Y-西妥昔单抗大1.5至2.5倍，这在对原位肿瘤进行成像时可能是关键的，并考虑到对肝脏等正常器官的辐射剂量。这项研究证明了86Y-panitumumab比86Y-cetuximab更有利的HER1靶向特性，用于通过PET成像无创性地评估MM的HER1状态。由于肝脏摄取率较低，基于Panitumab的免疫结合物在治疗中可能比相应的西妥昔单抗为基础的免疫结合物更好。
Malignant mesothelioma (MM), a rare form of cancer is often associated with previous exposure to fibrous minerals, such as asbestos. Asbestos exposure increases HER1-activity and expression in pre-clinical models. Additionally, HER1 over-expression is observed in the majority of MM cases. In this study, the utility of HER1-targeted chimeric IgG1, cetuximab, and a human IgG2, panitumumab, radiolabeled with 86Y, were evaluated for PET imaging to detect MM non-invasively in vivo, and to select an antibody candidate for radioimmunotherapy (RIT). Radioimmunoconjugates (RICs) of cetuximab and panitumumab were prepared by conjugation with CHX-A’’-DTPA followed by radiolabeling with 86Y. The HER1 expression of NCI-H226, NCI-H2052, NCI-H2452 and MSTO-211H human mesothelioma cells was characterized by flow cytometry. In vivo biodistribution, pharmacokinetic analysis, and PET imaging were performed in tumor bearing athymic mice. In vivo studies demonstrated high HER1 tumor uptake of both RICs. Significant reduction in tumor uptake was observed in mice co-injected with excess mAb (0.1 mg), demonstrating that uptake in the tumor was receptor specific. Significant differences were observed in the in vivo characteristics of the RICs. The blood clearance T½α of 86Y-cetuximab (0.9–1.1 h) was faster than 86Y-panitumumab (2.6–3.1 h). Also, the tumor area under the curve (AUC) to liver AUC ratios of 86Y-panitumumab were 1.5 to 2.5 times greater than 86Y-cetuximab as observed by the differences in PET tumor to background ratios, which could be critical when imaging orthotopic tumors and concerns regarding radiation doses to normal organs such as the liver. This study demonstrates the more favorable HER1-targeting characteristics of 86Y-panitumumab than 86Y-cetuximab for non-invasive assessment of the HER1 status of MM by PET imaging. Due to lower liver uptake, panitumumab based immunoconjugates may fare better in therapy than corresponding cetuximab based immunoconjugates.
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影响因子：
11.5
作者：
Milenic, DE;Garmestani, K;Brechbiel, MW
通讯作者：
Brechbiel, MW
石棉引起的肺部疾病：更新。
DOI：
10.1016/j.trsl.2009.01.004
发表时间：
2009-04
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
Kamp DW
通讯作者：
Kamp DW
影响因子：
5
作者：
Heelan, RT;Rusch, VW;Eisen, C
通讯作者：
Eisen, C
影响因子：
5.3
作者：
Gaafar, Rabab;Bahnassy, Abeer;Mokhtar, Nadia
通讯作者：
Mokhtar, Nadia
影响因子：
45.3
作者：
Garland, Linda L.;Rankin, Cathryn;Borden, Ernest C.
通讯作者：
Borden, Ernest C.