Anti-glioblastoma effect of a recombinant bispecific cytotoxin cotargeting human IL-13 and EGF receptors in a mouse xenograft model
Anti-glioblastoma effect of a recombinant bispecific cytotoxin cotargeting human IL-13 and EGF receptors in a mouse xenograft model
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DOI：
10.1007/s11060-007-9499-8
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发表时间：
2008-03-01
影响因子：
3.9
通讯作者：
Vallera, Daniel A.
中科院分区：
文献类型：
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作者：
Stish, Brad J.;Oh, Seunguk;Vallera, Daniel A.
为了提高IL-13细胞毒素（CT）的活性，将IL-13剪接到截断的白喉毒素（DT390）上，在其单链蛋白上添加表皮生长因子（EGF）。这种新的重组双特异性CT，称为DTEGF13，增强了对人胶质母细胞瘤细胞系U87MG （0.015 nM）和U118MG （0.02 nM）的杀伤能力。对肺癌细胞系Calu-3 （0.0018 nM）也有类似的增强作用。增强的活性不能用可结合的细胞因子数量增加来解释，因为单特异性DTEGF和DTIL13的组合并没有引起相同的增强活性。增强的活性依赖于同一单链分子上两种细胞因子的存在，并且杀伤是受体特异性的，因为靶受体阴性的白血病细胞不受高选择性DTEGF13的影响，并且可以用抗egfr和抗il -13抗体阻断细胞毒性。在异种移植侧腹肿瘤模型中，瘤内注射DTEGF13，而非单特异性DTEGF或DTIL13，可显著抑制裸鼠U87肿瘤的生长（P < 0.04）。在该模型中，DTEGF13的人EGF和IL-13成分分别与小鼠EGFR和IL-13R发生反应。这些研究表明，一种同时识别EGFR和IL-13R的新型共靶向药物比其单特异性对抗性药物更有效，并且DTEGF13对胶质母细胞瘤具有治疗优势。
To improve activity of a recombinant IL-13 cytotoxin (CT) comprised of IL-13 spliced to truncated diphtheria toxin (DT390), epidermal growth factor (EGF) was added to the same single chain protein. This new recombinant bispecific CT, called DTEGF13, enhanced the killing potency against the human glioblastoma lines, U87MG (0.015 nM) and U118MG (0.02 nM). A similar enhancement was observed against the lung carcinoma cell line, Calu-3 (0.0018 nM). Enhanced activity could not be explained by an increased number of cytokines available for binding since a combination of monospecific DTEGF and DTIL13 did not cause the same enhanced activity. Enhanced activity was dependent on the presence of both cytokines on the same single chain molecule and killing was receptor specific since target receptor negative leukemia cells were unaffected by the highly selective DTEGF13 and cytotoxicity could be blocked with anti-EGFR and anti-IL-13 antibodies. In a xenograft flank tumor model, intratumoral injection of DTEGF13, but not monospecific DTEGF or DTIL13, significantly inhibited the growth of established U87 tumors in nude mice (P < 0.04). In this model, the human EGF and IL-13 components of DTEGF13 are reactive with mouse EGFR and IL-13R, respectively. These studies show that a new co-targeting agent that simultaneously recognizes EGFR and IL-13R is more effective than its monospecific counterparts and that DTEGF13 has therapeutic advantages for glioblastoma.