Perfusion of 99Tcm-labeled CD105 Mab into kidneys from patients with renal carcinoma suggests that CD105 is a promising vascular target
Perfusion of 99Tcm-labeled CD105 Mab into kidneys from patients with renal carcinoma suggests that CD105 is a promising vascular target
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DOI：
10.1002/ijc.11699
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发表时间：
2004-04-10
影响因子：
6.4
通讯作者：
Kumar, S
中科院分区：
文献类型：
--
作者：
Costello, B;Chenggang, LG;Kumar, S
有强有力的已发表和未发表的证据表明，我们的CD105单抗E9与血管生成内皮细胞高度反应，可能是一种有用的试剂，可以靶向人类实体肿瘤的血管系统。由于Mab E9不与动物组织发生交叉反应，我们在此以人肾为体外模型，对其定位进行了评价。7例肾癌患者新鲜切除肾脏，经肾动脉灌注~(99)Tc(M)标记的纯化CD105单抗。在所有7例中，免疫核素显示明确的放射性热点的存在，这与术前MRI扫描和随后的组织病理学检查所确定的肿瘤位置相匹配。重要的是，在一个例子中，术前核磁共振扫描只发现了一个肿瘤，免疫核素扫描显示了两个不同的放射性热点。病理报告证实，额外的热点对应于一个血管丰富的小继发性肿瘤。这一发现的含义是，放射性标记的单抗E9可能在检测转移性疾病方面有用。当预先在2个肾脏内灌流未标记的单抗E9时，完全阻断了TC-99(M)标记的单抗E9的定位，证实了肿瘤的标记是特异的。取7个肾脏的肿瘤和正常组织标本，用伽玛计数器计数放射性。在所有病例中，与相应的正常肾脏相比，肿瘤中的放射性摄取更多。肾肿瘤患者的TC-99(M)中位数(每克湿重调整后)是正常肾组织的14.8倍(范围为4.8-113.0)(p<；0.007)。7例肿瘤组织冰冻切片免疫荧光染色显示，单抗E9在肿瘤微血管中定位强烈而均匀。有趣的是，偶见微血管段内皮细胞(ECs)的嵌合染色。也就是说，虽然大多数排列在微血管内的EC染色很深，但偶尔也有EC呈阴性。这不是染色的人工制品。由于CD105是一种增殖/激活相关抗原，因此未染色的内皮细胞可能是非血管生成的或凋亡的。有必要进行进一步的研究，以确定标记的CD105抗体在体内的药代动力学。这将使我们能够确定一项表面上非常成功的体外研究是否有可能在癌症患者中进行肿瘤成像/治疗性血管靶向。(C)2004年Wiley-Liss公司
There is strong published and unpublished evidence that our CD 105 Mab E9, which is highly reactive with angiogenic endothelial cells, could be a useful reagent to target the vasculature of solid tumors in man. Since Mab E9 does not cross-react with animal tissues, we undertook here to evaluate its localization using human kidney as an ex vivo model Perfusion was performed through the renal artery of Tc-99(m)-labeled purified CD 105 Mab in freshly excised kidneys from 7 patients with renal carcinoma. In all 7 cases, immunoscintigraphs showed the presence of well-defined radioactive hot spots, which matched the positions of the tumors as identified by presurgery MRI scans and subsequent histopathologic examination. Importantly, in one instance, where a presurgery MRI scan had identified only one tumor, immunoscintigraphs showed 2 distinct hot spots of radioactivity. The pathology report confirmed that the additional hot spot corresponded to a small secondary well-vascularized tumor. The implication of this finding is that the radiolabeled Mab, E9, may be of use in the detection of metastatic disease. That the labeling of tumors was specific was confirmed when prior perfusion of unlabeled mab E9 in 2 kidneys completely blocked the localization of Tc-99(m)-conjugated Mab E9. Radioactivity in samples of tumor and normal tissue taken from 7 kidneys was counted in a gamma counter. In all cases, there was a greater uptake of radioactivity in tumors compared with the corresponding normal kidneys. The median values, adjusted per gram wet weight, for Tc-99(m) were 14.8 times (range, 4.8-113.0) greater in kidney tumors than in normal kidney tissue (p < 0.007). Immunofluorescent staining of cryostat sections of tumor tissues in each of the 7 cases showed strong and uniform localization of Mab E9 in tumor microvessels. Interestingly, chimeric staining of endothelial cells (ECs) was seen in an occasional microvessel segment. That is, while most of the ECs lining a microvessel were strongly stained, an occasional EC was negative. This was not an artifact of staining. Unstained ECs may be nonangiogenic or apoptotic since CD 105 is a proliferation/activation-associated antigen. Further investigations are warranted to establish the pharmacokinetics of Tc-99(m)-labeled CD 105 antibody in vivo. This would enable us to determine whether an apparently highly successful ex vivo study has the potential for tumor imaging/therapeutic vascular targeting in patients with cancer. (C) 2004 Wiley-Liss, Inc.