Expression, engineering and characterization of the tumor-targeting heterodimeric immunocytokine F8-IL12.

Expression, engineering and characterization of the tumor-targeting heterodimeric immunocytokine F8-IL12.
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肿瘤靶向异二聚体免疫细胞因子 F8-IL12 的表达、工程设计和表征。

DOI：
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发表时间：
2010
期刊：
Protein engineering, design & selection : PEDS
影响因子：
--
通讯作者：
M. Kaspar
M. Kaspar
中科院分区：
--
文献类型：
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作者：
R. Sommavilla;N. Pasche;E. Trachsel;L. Giovannoni;C. Roesli;A. Villa;D. Neri;M. Kaspar

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促炎性细胞因子已在晚期癌症患者中使用数年，但它们的施用通常与严重毒性相关，妨碍它们应用于治疗活性方案。这个问题可以通过使用免疫细胞因子（与抗体或抗体片段融合的细胞因子）来克服，所述免疫细胞因子选择性地将活性细胞因子递送到肿瘤环境。临床前和最近的临床结果证实，这种方法是一种非常有前途的途径。我们设计了一种免疫细胞因子，由特异性针对纤连蛋白外域A的scFv（F8）和非常有效的人细胞因子白细胞介素-12（IL-12）组成。IL 12的异二聚体性质允许基于两个亚基（p35和p40）与scFv的不同组合来工程化各种免疫细胞因子形式。与单体或同二聚体细胞因子相比，异二聚体免疫细胞因子的构建提出了许多挑战，例如基因给药、稳定的高产率表达以及良好生产规范（GMP）纯化和表征。在本文中，我们描述了成功的构建，表征和生产的异源二聚体免疫细胞因子F8-IL 12。该可行性研究的积极结果现在导致F8-IL 12的GMP生产，其将很快进入临床试验。
Proinflammatory cytokines have been used for several years in patients with advanced cancer but their administration is typically associated with severe toxicity hampering their application to therapeutically active regimens. This problem can be overcome by using immunocytokines (cytokines fused to antibody or antibody fragments) which selectively deliver the active cytokine to the tumor environment. Preclinical and recent clinical results confirmed that this approach is a very promising avenue to go. We designed an immunocytokine consisting of the scFv(F8) specific to extra-domain A of fibronectin and the very potent human cytokine interleukin-12 (IL12). The heterodimeric nature of IL12 allows the engineering of various immunocytokine formats, based on different combinations of the two subunits (p35 and p40) together with the scFv. In comparison to monomeric or homodimeric cytokines, the construction of a heterodimeric immunocytokine poses many challenges, e.g. gene dosing, stable high-yield expression as well as good manufacture practice (GMP) purification and characterization. In this paper, we describe the successful construction, characterization and production of the heterodimeric immunocytokine F8-IL12. The positive outcome of this feasibility study leads now to GMP production of F8-IL12, which will soon enter clinical trials.
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