A bispecific recombinant cytotoxin (DTEGF13) targeting human interleukin-13 and epidermal growth factor receptors in a mouse xenograft model of prostate cancer
A bispecific recombinant cytotoxin (DTEGF13) targeting human interleukin-13 and epidermal growth factor receptors in a mouse xenograft model of prostate cancer
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DOI：
10.1158/1078-0432.ccr-07-0938
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发表时间：
2007-11-01
影响因子：
11.5
通讯作者：
Vallera, Daniel A.
中科院分区：
文献类型：
--
作者：
Stish, Brad J.;Chen, Hua;Vallera, Daniel A.
目的：过表达的细胞因子受体被认为是靶向前列腺癌的新生物制剂的有效靶点。然而，目前的试剂在功效上是有限的。我们的目标是确定用新的双特异性细胞毒素同时靶向两个已建立的靶点（表皮生长因子受体和白细胞介素-13（IL-13）受体）的优点，其中EGF和IL-13细胞因子都被克隆到具有截短的白喉毒素（DT 390）的相同单链分子上。体外实验测量了双特异性DTEGF 13的效力，并将其活性与其单特异性对应物DTEGF和DTIL 13进行了比较。我们确定是否存在的两种细胞因子配体的同一分子是负责其上级活动。在体内，将DTEGF 13 i.t.结果：DTEGF 13在体外对人前列腺癌细胞株的杀伤作用强于单特异性细胞毒素。增强的活性与同一单链分子上两种细胞因子的存在有关，而不是归因于增强的结合能力。杀伤是受体特异性的。细胞毒性可以用抗EGF和抗IL-13抗体阻断。在体内，DTEGF 13，而不是单特异性DTEGF或DTIL 13，显着抑制已建立的PC-3裸鼠肿瘤的生长（P <0.0001）。结论：这些数据首次表明，同时靶向细胞因子受体与同一分子上的两个配体具有显着的抗癌优势。在人DTEGF 13与小鼠交叉反应的动物模型中，DTEGF 13在检查侵袭性前列腺肿瘤进展方面非常有效，并且具有合理的耐受性。
Purpose: Overexpressed cytokine receptors are considered valid targets for new biologicals targeting prostate cancer. However, current reagents are limited in efficacy. Our goal was to determine the advantages of simultaneously targeting two established targets, epidermal growth factor receptor and interleukin-13 (IL-13) receptor, with a new bispecific cytotoxin in which both EGF and IL-13 cytokines were cloned onto the same single-chain molecule with truncated diphtheria toxin (DT390).Experimental Design: In vitro experiments measured the potency of bispecific DTEGF13 and compared its activity to its monospecific counterparts, DTEGF and DTIL13. We determined whether the presence of both cytokine ligands on the same molecule was responsible for its superior activity. In vivo, DTEGF13 was given i.t. to athymic nude mice with established PC-3 human prostate cancer tumor xenografts on their flanks.Results: In vitro, DTEGF13 was more potent than the monospecific cytotoxins against human prostate cancer lines. Enhanced activity was related to the presence of both cytokines on the same single-chain molecule and was not attributed to enhanced binding capacity. Killing was receptor specific. Cytotoxicity could be blocked with anti-EGF and anti - IL-13 antibodies. In vivo, DTEGF13, but not monospecific DTEGF or DTIL13, significantly inhibited the growth of established PC-3 tumors in nude mice (P < 0.0001).Conclusions: These data show for the first time that simultaneous targeting of cytokine receptors with two ligands on the same molecule has pronounced anticancer advantages. In an animal model in which human DTEGF13 is cross-reactive with mouse, DTEGF13 was highly effective in checking aggressive prostate tumor progression and was reasonably tolerated.