Epstein A L, Khawli L A, Hornick J L, Taylor C R
Department of Pathology, University of Southern California School of Medicine, Los Angeles 90033, USA.
Cancer Res. 1995 Jun 15;55(12):2673-80.
mAbs reactive with epitopes expressed on tumor vessels were evaluated as universal delivery agents of peptides with vasoactive properties to enhance the uptake of macromolecules in tumors. Unlike other reported approaches to target tumor vessels, a mAb designated TV-1 targets a basement membrane antigen that is found in all tissues but that is accessible only in tumor vessels, making it an alternative vehicle for the delivery of biologically active peptides to tumors. A panel of 30 monoclonal and polyclonal antibodies was screened by immunohistochemistry on sections of human tumors, normal vascular endothelium, and connective tissues. Five antibodies were chosen for in vivo evaluation, including two antifibronectin antibodies (TV-1, HFN 7.1), one anti-basic fibroblast growth factor antibody (anti-BFGF), and two antibodies reactive with a mesenchymal cell antigen (TP-1, TP-3). Three nude mouse tumor models characterized by varying degrees of vascularization (low to high) were used. After chemical conjugation to interleukin 2 (IL-2), these antibodies were used to pretreat tumor-bearing nude mice 3 h before injection with a radiolabeled mAb directed to the transplanted tumors. Pretreatment with TV-1/IL-2 or HFN 7.1/IL-2 produced a 3-fold higher tumor uptake of radiolabel compared to control mice pretreated with mAb alone. The other three vasoactive immunoconjugates failed to show significant increases in these tumor models. When TV-1/IL-2 was compared with the specific vasoconjugate (Lym-1/IL-2) as a pretreatment in the Raji lymphoma model, which has low vascularization, TV-1/IL-2 yielded approximately 60% of the tumor uptake seen with Lym-1/IL-2. In comparison, pretreatment with TV-1/IL-2 in the LS174T colon carcinoma model, which has high vascularization, yielded approximately the same tumor uptake seen with the B72.3/IL-2 vasoconjugate, which directly targets the tumor cells. These studies demonstrate that a mAb directed against fibronectin in the endothelial subcellular matrix can be used to deliver vasoactive agents to tumors.
与肿瘤血管上表达的表位发生反应的单克隆抗体被评估为具有血管活性特性的肽的通用递送剂，以增强肿瘤中大分子的摄取。与其他报道的靶向肿瘤血管的方法不同，一种名为TV-1的单克隆抗体靶向一种在所有组织中都存在但仅在肿瘤血管中可及的基底膜抗原，这使其成为向肿瘤递送生物活性肽的另一种载体。通过免疫组织化学在人肿瘤、正常血管内皮和结缔组织切片上筛选了一组30种单克隆和多克隆抗体。选择了5种抗体进行体内评估，包括两种抗纤连蛋白抗体（TV-1、HFN 7.1）、一种抗碱性成纤维细胞生长因子抗体（抗BFGF）和两种与间充质细胞抗原发生反应的抗体（TP-1、TP-3）。使用了三种具有不同血管化程度（低到高）的裸鼠肿瘤模型。在与白细胞介素2（IL-2）进行化学偶联后，这些抗体在注射针对移植肿瘤的放射性标记单克隆抗体前3小时用于预处理荷瘤裸鼠。与单独用单克隆抗体预处理的对照小鼠相比，用TV-1/IL-2或HFN 7.1/IL-2预处理使放射性标记物在肿瘤中的摄取提高了3倍。在其他三种血管活性免疫偶联物在这些肿瘤模型中未显示出显著增加。当在血管化程度低的Raji淋巴瘤模型中，将TV-1/IL-2与特异性血管偶联物（Lym-1/IL-2）作为预处理进行比较时，TV-1/IL-2产生的肿瘤摄取约为Lym-1/IL-2的60%。相比之下，在血管化程度高的LS174T结肠癌模型中，用TV-1/IL-2预处理产生的肿瘤摄取与直接靶向肿瘤细胞的B72.3/IL-2血管偶联物所见的肿瘤摄取大致相同。这些研究表明，一种针对内皮亚细胞基质中纤连蛋白的单克隆抗体可用于向肿瘤递送血管活性药物。
