Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy
Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy
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DOI：
10.1158/1535-7163.mct-13-0282
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发表时间：
2014-01-01
影响因子：
5.7
通讯作者：
Mueller, Dafne
中科院分区：
文献类型：
--
作者：
Kermer, Vanessa;Hornig, Nora;Mueller, Dafne
影响调节免疫应答的细胞因子受体网络对于癌症免疫治疗具有巨大的潜力。虽然迄今为止通过关注共同γ链（γ c）受体家族和TNF受体超家族的单个成员已经获得了令人鼓舞的结果，但可能需要联合策略来进一步提高抗肿瘤反应的有效性。在这里，我们提出了白细胞介素（IL）-15和4-1BBL在一个单一的肿瘤导向分子的组合。因此，产生了三功能抗体融合蛋白，其由肿瘤特异性重组抗体、连接至IL-15 R α链（RD）的片段的IL-15和4-1BBL的胞外结构域组成。在可溶性和靶向形式中，三功能抗体融合蛋白RD_IL-15_scFv_ 4-1BBL显示刺激活化的T细胞增殖并诱导T细胞细胞毒性，其程度与双功能scFv_ RD_ IL-15融合蛋白相似。另一方面，在靶向形式中，三功能融合蛋白在诱导未刺激的外周血单核细胞（PBMC）的T细胞增殖和IFN-γ释放方面有效得多。在此，额外的信号增强可归因于4-1BBL的共刺激活性，表明在一个分子中同时呈递IL-15和4-1BBL的明显益处。此外，三功能抗体融合蛋白比相应的双功能融合蛋白在体内减少肿瘤小鼠模型中的转移更有效。因此，IL-15和4-BBL以三功能抗体融合蛋白的形式的靶向组合是用于癌症免疫治疗的有希望的新方法。（C）2013年AACR。
Influencing the cytokine receptor network that modulates the immune response holds great potential for cancer immunotherapy. Although encouraging results have been obtained by focusing on individual members of the common gamma-chain (gamma c) receptor family and TNF receptor superfamily so far, combination strategies might be required to further improve the effectiveness of the antitumor response. Here, we propose the combination of interleukin (IL)-15 and 4-1BBL in a single, tumor-directed molecule. Therefore, a trifunctional antibody fusion protein was generated, composed of a tumor-specific recombinant antibody, IL-15 linked to a fragment of the IL-15R alpha chain (RD) and the extracellular domain of 4-1BBL. In soluble and targeted forms, the trifunctional antibody fusion protein RD_IL-15_scFv_ 4-1BBL was shown to stimulate activated T-cell proliferation and induce T-cell cytotoxicity to a similar degree as the bifunctional scFv_ RD_ IL-15 fusion protein. On the other hand, in targeted form, the trifunctional fusion protein was much more effective in inducing T-cell proliferation and IFN-gamma release of unstimulated peripheral blood mononuclear cells (PBMC). Here, the additional signal enhancement could be attributed to the costimulatory activity of 4-1BBL, indicating a clear benefit for the simultaneous presentation of IL-15 and 4-1BBL in one molecule. Furthermore, the trifunctional antibody fusion protein was more effective than the corresponding bifunctional fusion proteins in reducing metastases in a tumor mouse model in vivo. Hence, the targeted combination of IL-15 and 4-BBL in the form of a trifunctional antibody-fusion protein is a promising new approach for cancer immunotherapy. (C)2013 AACR.