A novel bispecific ligand-directed toxin designed to simultaneously target EGFR on human glioblastoma cells and uPAR on tumor neovasculature.
A novel bispecific ligand-directed toxin designed to simultaneously target EGFR on human glioblastoma cells and uPAR on tumor neovasculature.
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DOI：
10.1007/s11060-010-0392-5
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发表时间：
2011-06
影响因子：
3.9
通讯作者：
Vallera, Daniel A.
中科院分区：
文献类型：
--
作者：
Tsai, Alexander K.;Oh, Seunguk;Chen, Hua;Shu, Yanqun;Ohlfest, John R.;Vallera, Daniel A.
为了靶向人脑胶质母细胞瘤，我们组装了一种双特异性配体导向毒素(BLT)，称为EGFATFKDEL，它由人表皮生长因子、一段尿激酶和截短的假单胞菌外毒素(PE38)组成。通过突变PE38分子上的七个免疫优势B细胞表位来创建新的试剂EGFATFKDEL 7mut，从而降低了免疫原性。在体外，该药物选择性地杀死了几个人胶质母细胞瘤细胞系。EGFATFKDEL是我们的第一个BLT，旨在同时靶向实体肿瘤上的EGFR和肿瘤新生血管上的uPAR。体外实验表明，该药物对胶质母细胞瘤细胞株和人脐静脉内皮细胞(HUVEC)均有效。此外，与类似的单特异性药物EGFKDEL和ATFKDEL相比，这种双特异性药物显示出与过表达的表皮生长因子受体和尿激酶受体的结合增强。在体内，一种侵袭性的人类胶质母细胞瘤细胞系被基因标记为萤火虫荧光素酶报告基因，并被注射到裸鼠的侧翼。瘤内注射EGFATFKDEL 7mut可根除一半以上的小鼠的小肿瘤，这些小鼠在肿瘤接种后至少100天无瘤存活。ATFKDEL主要针对肿瘤新生血管，阻止了肿瘤的生长，但在大多数情况下并没有导致无肿瘤的小鼠。通过不保护小鼠的无关的BLT对照治疗，显示了特异性。最后，免疫活性小鼠的免疫实验显示，EGFATFKDEL 7mut处理组的抗毒素产生显著减少。因此，EGFATFKDEL 7mut是治疗该模型小鼠胶质母细胞瘤的有效药物，值得进一步研究。
A bispecific ligand-directed toxin (BLT), called EGFATFKDEL, consisting of human epidermal growth factor, a fragment of urokinase, and truncated pseudomonas exotoxin (PE38) was assembled in order to target human glioblastoma. Immunogenicity was reduced by mutating seven immunodominant B-cell epitopes on the PE38 molecule to create a new agent, EGFATFKDEL 7mut. In vitro, the drug selectively killed several human glioblastoma cell lines. EGFATFKDEL is our first BLT designed to simultaneously target EGFR on solid tumors and uPAR on the tumor neovasculature. In vitro assays revealed that the agent is effective against glioblastoma cell lines as well as human umbilical vein endothelial cells (HUVEC). Additionally, the bispecific drug displayed enhanced binding to overexpressed epidermal growth factor receptor and urokinase receptor when compared to similar monospecific drugs, EGFKDEL and ATFKDEL. In vivo, an aggressive human glioblastoma cell line was genetically marked with a firefly luciferase reporter gene and administered to the flanks of nude mice. Treatment with intratumoral injections of EGFATFKDEL 7mut eradicated small tumors in over half of the treated mice, which survived with tumor free status at least 100 days post tumor inoculation. ATFKDEL, which primarily targets the tumor neovasculature, prevented tumor growth but did not result in tumor-free mice in most cases. Specificity was shown by treating with an irrelevant BLT control which did not protect mice. Finally, immunization experiments in immunocompetent mice revealed significantly reduced anti-toxin production in EGFATFKDEL 7mut treated groups. Thus, EGFATFKDEL 7mut is an effective drug for glioblastoma therapy in this murine model and warrants further study.
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影响因子：
6.4
作者：
Rustamzadeh, Edward;Hall, Walter A.;Vallera, Daniel A.
通讯作者：
Vallera, Daniel A.
影响因子：
11.5
作者：
Stish, Brad J.;Chen, Hua;Vallera, Daniel A.
通讯作者：
Vallera, Daniel A.
影响因子：
11.5
作者：
Vallera, DA;Todhunter, DA;Chen, H
通讯作者：
Chen, H
DOI：
10.1073/pnas.0804851105
发表时间：
2008-08-12
影响因子：
11.1
作者：
Onda, Masanori;Beers, Richard;Pastan, Ira
通讯作者：
Pastan, Ira
影响因子：
3.9
作者：
Mori, T;Abe, T;Hori, S
通讯作者：
Hori, S