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首页> 外文期刊>Molecular cancer therapeutics >Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy
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Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy

机译：将IL-15和4-1BBL在三官能融合蛋白中结合抗体的术语癌症免疫疗法

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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.
机译：影响调节免疫反应的细胞因子受体网络具有巨大癌症免疫疗法的潜力。虽然通过专注于常见的γ-链（γc）受体家庭和TNF受体超家族的个体成员来获得令人鼓舞的结果，但可能需要组合策略来进一步提高抗肿瘤反应的有效性。这里，我们提出了白细胞介素（IL）-15和4-1BBL在单个肿瘤的分子中的组合。因此，产生三官能抗体融合蛋白，由肿瘤特异性重组抗体，IL-15与IL-15Rα链（RD）的片段和4-1Bbl的细胞外结构域连接。以可溶性和靶向形式，示出三官能抗体融合蛋白RD_IL-15_SCFV_4-1BBL刺激活性T细胞增殖，并诱导T细胞细胞毒性与双功能SCFV_RD_ IL-15融合蛋白相似的程度。另一方面，在靶向形式中，三官能融合蛋白在诱导T细胞增殖和非刺激外周血单核细胞（PBMC）的IFN-Gamma释放方面更有效。这里，额外的信号增强可归因于4-1BBL的共和率活性，表明在一个分子中同时呈现IL-15和4-1BBL的明显益处。此外，三官能抗体融合蛋白比在体内减少肿瘤小鼠模型中的转移中的相应双官能融合蛋白更有效。因此，IL-15和4-BBL以三官能抗体融合蛋白形式的靶向组合是癌症免疫疗法的有希望的新方法。 （c）2013 AACR。

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