A high-affinity human antibody that targets tumoral blood vessels
A high-affinity human antibody that targets tumoral blood vessels
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DOI：
10.1182/blood.v94.1.192.413k22_192_198
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发表时间：
1999-07-01
期刊：
影响因子：
20.3
通讯作者：
Zardi, L
中科院分区：
文献类型：
--
作者：
Tarli, L;Balza, E;Zardi, L
血管生成是许多侵袭性肿瘤和其他相关疾病的特征。能够特异性结合新生血管而不是成熟血管的分子可以用作选择性载体，因此将打开诊断和治疗的机会。我们研究了ED-B癌胚区纤连蛋白的分布，血管生成的标志物，在四个不同的肿瘤动物模型：F9小鼠畸胎癌，SKMEL-28人黑色素瘤，N592人小细胞肺癌，和C51人结肠癌。在所有这些实验模型中，我们观察到当肿瘤处于指数生长阶段时，在新生血管结构周围含有ED-B结构域的纤连蛋白同种型的积累，但不在缓慢生长阶段。然后，我们进行了生物分布的研究，在小鼠皮下植入F9小鼠畸胎癌，使用高亲和力的人抗体片段（L19）针对纤连蛋白的ED-B结构域。放射性标记的L19，而不是无关的抗溶菌酶抗体片段（D1.3），有效地定位在肿瘤血管。在注射后3小时观察到肿瘤中积累的L19的最大剂量（8.2%注射剂量/克）。由于抗体片段从循环中快速清除，在3、5和24小时分别获得1.9、3.7和11.8的肿瘤-血液比。L19的肿瘤靶向性能在注射抗体的0.7至10 μ g范围内不是剂量依赖性的。24小时内肿瘤血管中定位的放射性积分比同一时间段内血液中放射性积分高70倍以上，以每克组织或液体标准化。这些研究结果定量地表明，新形成的血管可以选择性地在体内靶向使用特异性抗体，并表明，L19可能是临床实用的免疫闪烁检测患者的血管生成。(C)1999年，美国血液学会。
Angiogenesis is a characteristic feature of many aggressive tumors and of other relevant disorders. Molecules capable of specifically binding to new-forming blood vessels, but not to mature vessels, could be used as selective vehicles and would, therefore, open diagnostic and therapeutic opportunities. We have studied the distribution of the ED-B oncofetal domain of fibronectin, a marker of angiogenesis, in four different tumor animal models: the F9 murine teratocarcinoma, SKMEL-28 human melanoma, N592 human small cell lung carcinoma, and C51 human colon carcinoma. In all of these experimental models we observed accumulation of the fibronectin isoform containing the ED-B domain around neovascular structures when the tumors were in the exponentially growing phase, but not in the slow-growing phase. Then we performed biodistribution studies in mice bearing a subcutaneously implanted F9 murine teratocarcinoma, using a high-affinity human antibody fragment (L19) directed against the ED-B domain of fibronectin. Radiolabeled L19, but not an irrelevant anti lysozyme antibody fragment (D1.3), efficiently localizes in the tumoral vessels. The maximal dose of L19 accumulated in the tumor was observed 3 hours after injection (8.2% injected dose per gram). By virtue of the rapid clearance of the antibody fragment from the circulation, tumor-to-blood ratios of 1.9, 3.7, and 11.8 were obtained at 3, 5, and 24 hours, respectively. The tumor targeting performance of L19 was not dose-dependent in the 0.7 to 10 mu g range of injected antibody. The integral of the radioactivity localized in tumoral vessels over 24 hours was greater than 70-fold higher than the integral of the radioactivity in blood over the same time period, normalized per gram of tissue or fluid. These findings quantitatively show that new-forming blood vessels can selectively be targeted in vivo using specific antibodies, and suggest that L19 may be of clinical utility for the immunoscintigraphic detection of angiogenesis in patients. (C) 1999 by The American Society of Hematology.