An Antibody Fusion Protein for Cancer Immunotherapy Mimicking IL-15 trans-Presentation at the Tumor Site
An Antibody Fusion Protein for Cancer Immunotherapy Mimicking IL-15 trans-Presentation at the Tumor Site
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DOI：
10.1158/1535-7163.mct-12-0019
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发表时间：
2012-06-01
影响因子：
5.7
通讯作者：
Mueller, Dafne
中科院分区：
文献类型：
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作者：
Kermer, Vanessa;Baum, Volker;Mueller, Dafne
驱动免疫反应的细胞因子是癌症免疫治疗的有力工具，但其应用通常受到严重的全身毒性的限制。通过抗体-细胞因子融合蛋白的方法进行靶向治疗，可以将细胞因子的活性集中到肿瘤部位，从而减少不必要的副作用。在这里，我们研究了通过加入IL-15R阿尔法链片段，模拟生理学转呈，以靶向方式提高白介素15呈递效率的可能性。因此，我们构建了一种抗体细胞因子融合蛋白(scFv_RD_IL-15)，该融合蛋白由针对肿瘤间质成纤维细胞激活蛋白(FAP)的抗体部分、延伸的IL-15Rα苏司结构域(RD)和IL-15组成，以可溶性和靶向形式显示抗体介导的特异性结合和细胞因子活性。与相应的不含RD的抗体融合蛋白(scFv_IL-15)的比较分析表明，ScFv_RD_IL-15在溶液中增强了对Mo7e(IL-15Rβ-Gamma)细胞的刺激活性，降低了对CTLL-2(IL-15Rα-Gamma)的增殖反应，而在FAP靶向即膜结合形式下，获得了类似的CTLL-2(IL-15RαβGamma)细胞的增殖。此外，ScFv_RD_IL-15以其可溶性和靶向结合的形式分别对未刺激和激活的T细胞具有更强的增殖和细胞毒作用。此外，在肺转移瘤小鼠模型中的体内分析表明，与非靶向或RD缺失的IL-15融合蛋白相比，scFv_RD_IL-15具有更好的抗肿瘤作用。因此，肿瘤导向转导IL-15并以抗体融合蛋白的形式与RD结合似乎是进一步提高IL-15抗肿瘤作用的一种有前途的方法。摩尔癌症治疗；11(6)；1279-88。(C)2012年AACR。
Cytokines driving the immune response are powerful tools for cancer immunotherapy, but their application is generally limited by severe systemic toxicity. Targeted approaches by means of antibody-cytokine fusion proteins might enable focus on the cytokine activity to the tumor site, thereby reducing unwanted side effects. Here, we investigated the possibility to improve the efficiency of interleukin (IL)-15 presentation in a targeted approach by the incorporation of an IL-15R alpha chain fragment, mimicking physiologic trans-presentation. Therefore, an antibody cytokine fusion protein (scFv_RD_IL-15) composed of an antibody moiety targeting the tumor stromal fibroblast activation protein (FAP), an extended IL-15R alpha sushi domain (RD) and IL-15 was generated, exhibiting antibody-mediated specific binding and cytokine activity in soluble and targeted form. Comparative analysis with a corresponding antibody fusion protein devoid of RD (scFv_IL-15) showed for scFv_RD_IL-15 in solution enhanced stimulatory activity on Mo7e (IL-15R beta gamma) cells and reduced proliferation response on CTLL-2 (IL-15R alpha beta gamma) cells, while in FAP-targeted, that is, membrane-bound form, comparable proliferation of CTLL-2 (IL-15R alpha beta gamma) cells was obtained. In addition, scFv_RD_IL-15 achieved in its soluble and target-bound form stronger proliferation and cytotoxicity on unstimulated and activated T cells, respectively. Furthermore, in vivo analysis in a lung metastasis tumor mouse model revealed a superior antitumor effect for scFv_RD_IL-15 in comparison with that obtained by an untargeted or RD missing version of IL-15 fusion protein. Thus, tumor-directed transpresentation of IL-15 in association with RD in form of an antibody fusion protein seems to be a promising approach to further improve the antitumor effect of IL-15. Mol Cancer Ther; 11(6); 1279-88. (C)2012 AACR.