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Tri-functional antibody- fusion proteins for cancer immunotherapy

用于癌症免疫治疗的三功能抗体融合蛋白

基本信息

批准号：
256957568
负责人：
Dr. Dafne Müller
金额：
--
依托单位：
Institut für Zellbiologie und Immunologie (IZI)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/256957568?language=en
关键词：
Tri functional antibody fusion proteins

项目摘要

The antitumor potential of cytokine/ligand-receptor interactions that modulate an immune response has moved into the spotlight of cancer treatment strategies. Here, we propose an approach with tri-functional antibody-fusion proteins composed of a tumor-directed recombinant antibody and two different cytokines/chemokines. According to the concept, target-directed delivery of appropriate combinations of cytokine/ chemokine to the tumor site will support an efficient local antitumor immune response. Thereby, targeting should reduce the risk of systemic toxicity and autoimmune effects, while the combinatorial use of different immune-modulatory molecules should allow overcoming tumor evasion mechanisms. In the preceding project we have already successfully generated antibody-fusion proteins with IL-15 linked to part of the IL-15Ralpha chain and generated first tri-functional fusion proteins by the additional incorporation of the costimulatory ligand 4-1BBL. Thus, improved immune-stimulatory activity was achieved by the targeted form in vitro and antitumoral effects were reported in vivo. In light of these encouraging results, we aim to continue developing this concept by improving and expanding the generation of tri-functional antibody-fusion proteins, thereby meeting criteria of simple configuration, minimal size and good accessibility of all compounds in soluble and targeted form. Furthermore, we will focus on the combination of IL-15 with different ligands either of the TNF-superfamily (OX40L, GITRL, LIGHT) or the chemokine CCL-family (CCL16, CCL21). We will analyze the influence of the configuration of these molecules on the activity displayed in soluble and targeted form and their impact on the immune response of T cells and NK cells in vitro. Subsequently, murine versions of the most promising tri-functional fusion proteins will be generated and their antitumor potential evaluated in an immune competent tumor mouse model. Thus, insight into the implementation and prospect of this innovative approach is expected to be gained.

调节免疫应答的细胞因子/配体-受体相互作用的抗肿瘤潜力已经成为癌症治疗策略的焦点。在这里，我们提出了一种方法与三功能抗体融合蛋白组成的肿瘤导向的重组抗体和两种不同的细胞因子/趋化因子。根据这一概念，将细胞因子/趋化因子的适当组合靶向递送至肿瘤部位将支持有效的局部抗肿瘤免疫反应。因此，靶向应该降低全身毒性和自身免疫效应的风险，而不同免疫调节分子的组合使用应该允许克服肿瘤逃避机制。在前面的项目中，我们已经成功地产生了IL-15与IL-15 R α链部分连接的抗体融合蛋白，并通过额外掺入共刺激配体4-1BBL产生了第一个三功能融合蛋白。因此，通过体外靶向形式实现了改善的免疫刺激活性，并报道了体内抗肿瘤作用。鉴于这些令人鼓舞的结果，我们的目标是通过改进和扩大三功能抗体融合蛋白的产生来继续发展这一概念，从而满足所有化合物以可溶性和靶向形式的简单构型、最小尺寸和良好可及性的标准。此外，我们将重点关注IL-15与TNF超家族（OX 40 L，GITRL，LIGHT）或趋化因子CCL家族（CCL 16，CCL 21）的不同配体的组合。我们将分析这些分子的构型对以可溶性和靶向形式显示的活性的影响，以及它们对体外T细胞和NK细胞的免疫应答的影响。随后，将产生最有希望的三功能融合蛋白的鼠版本，并在免疫活性肿瘤小鼠模型中评价其抗肿瘤潜力。因此，深入了解这种创新方法的实施和前景。