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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Targeting tumor vasculature endothelial cells and tumor cells for immunotheray of human melanoma in a mouse xenograft model
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Targeting tumor vasculature endothelial cells and tumor cells for immunotheray of human melanoma in a mouse xenograft model

机译：在小鼠异种移植模型中靶向肿瘤血管系统内皮细胞和肿瘤细胞进行人黑素瘤的免疫治疗

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An immunotherapy treatment for cancer that targets both the tumor vasculature and tumor cells has shown promising results in a severe combined immunodeficient mouse xenograft model of human melanoma. The treatment involves systemic delivery of an immunoconjugate molecule composed of a tumor-targeting domain conjugated to the Fc effector domain of human IgG1. The effector domain induces a cytolytic immune response against the targeted cells by natural killer cells and complement. Two types of targeting domains were used. One targeting domain is a human singlechain Fv molecule that binds to a chondroitin sulfate proteoglycan expressed on the surface of most human melanoma cells. Another targeting domain is factor VII (fVII), a zymogen that binds with high specificity and affinity to the transmembrane receptor tissue factor (TF) to initiate the blood coagulation cascade. TF is expressed by endothelial cells lining the tumor vasculature but not the normal vasculature, and also by many types of tumor cells including melanoma. Because the binding of a fVII immunoconjugate to TF might cause disseminated intravascular coagulation, the active site of fVII was mutated to inhibit coagulation without affecting the affinity for TF. The immunoconjugates were encoded as secreted molecules in a replication-defective adenovirus vector, which was injected into the tail vein of severe combined immunodeficient mice. The results demonstrate that a mutated fVII immunoconjugate, administered separately or together with a single-chain Fv immunoconjugate that binds to the tumor cells, can inhibit
机译：针对肿瘤血管和肿瘤细胞的癌症免疫疗法在人类黑素瘤的严重联合免疫缺陷小鼠异种移植模型中显示出令人鼓舞的结果。该治疗涉及全身递送由缀合至人IgG1的Fc效应子结构域的肿瘤靶向结构域组成的免疫缀合物分子。效应域通过自然杀伤细胞和补体诱导针对靶细胞的溶细胞免疫应答。使用了两种类型的定位域。一个靶向结构域是人单链Fv分子，该分子与大多数人黑素瘤细胞表面表达的硫酸软骨素蛋白聚糖结合。另一个靶向结构域是因子VII（fVII），一种酶原，它与跨膜受体组织因子（TF）高特异性和亲和力结合，从而启动凝血级联反应。 TF由衬在肿瘤脉管系统中的内皮细胞而非正常脉管系统表达，还由包括黑素瘤在内的多种类型的肿瘤细胞表达。由于fVII免疫偶联物与TF的结合可能引起弥散性血管内凝血，因此fVII的活性位点发生了突变，可以抑制凝血而不会影响对TF的亲和力。免疫缀合物被编码为复制缺陷型腺病毒载体中的分泌分子，该载体被注射入严重合并免疫缺陷小鼠的尾静脉。结果表明，突变的fVII免疫缀合物可以单独或与结合肿瘤细胞的单链Fv免疫缀合物一起施用，可以抑制

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