增强对IL-2受体β亚基的亲和力,通过重塑肿瘤微环境,增强IL-2在各种肿瘤模型中的抗肿瘤功效。

IF 3.4 3区 医学 Q2 IMMUNOLOGY
Ernesto Relova-Hernández, Ana Beatriz Díaz-Bravo, Rodrigo Pedroso, Miguel Ángel Gonzalez-Cruz, Tania Gómez, Eliany Arias, Dayana Pérez-Martínez, Rydell Álvarez-Arzola, Janet Avellanet, Lisandra Padrón, Addys González Palomo, Luis Graça, Kalet León, Gertrudis Rojas, Tania Carmenate
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引用次数: 0

摘要

用高剂量重组白细胞介素2 (IL-2)治疗癌症的主要局限性是高毒性和调节性T细胞的不期望扩增。IL-2突变变体(突变蛋白)的产生改变了对IL-2受体(IL-2R)不同链的亲和力,允许在克服其毒性的同时选择性刺激效应细胞。由于增加IL-2对IL-2R β链的亲和力会导致更好的抗肿瘤效果,我们在之前的工作中使用噬菌体展示技术生成了一组这些突变蛋白。重组fc融合蛋白,包括这些变体,比含有IL-2的变体(IL-2Fc)具有更好的可发育性和更好的体内效应。在这里,我们评估了一种名为superbeta 834 (SB834Fc)的改进的mutein,并对其特性进行了全面的表征。该蛋白在3LL-D122、B16F10、CT26、MC38、4T1等5种小鼠肿瘤模型中均表现出极低剂量下比IL-2Fc更强的抗肿瘤作用。与其他IL-2变体不同,SB834Fc作为单一疗法,在注射治疗方案中表现出抗肿瘤作用。这种抗肿瘤作用与脾和肿瘤微环境中效应T细胞的强刺激相一致,尽管保持相同水平的Treg刺激,但远高于IL-2Fc观察到的效果。此外,从人类健康供体分离的CD8+ T细胞中证实了诱导增殖,突出了其转化价值。这些结果支持SB834Fc融合蛋白作为开发基于IL-2的新型癌症免疫疗法的合适候选蛋白。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Enhanced affinity for the IL-2 receptor β subunit potently increases antitumor efficacy of IL-2 across various tumor models by reshaping the tumor microenvironment.

The main limitations of cancer treatment with high doses of recombinant interleukin 2 (IL-2) are high toxicity and the undesired expansion of regulatory T cells. The generation of IL-2 mutated variants (muteins) with changes in the affinity for different chains of the IL-2 receptor (IL-2R) allows selective stimulation of effector cells while overcoming its toxicity. As increasing the IL-2 affinity for the IL-2R beta chain leads to better antitumor effect, we generated a group of these muteins using phage display technology, in a previous work. Recombinant Fc-fusion proteins, including these variants, resulted in improved developability properties and better in vivo effect than variants containing the IL-2 (IL-2Fc). Here, we assessed one such improved mutein, named superbeta 834 (SB834Fc), and performed a comprehensive characterization of its properties. This mutein showed a stronger antitumor effect than IL-2Fc in 5 murine tumor models: 3LL-D122, B16F10, CT26, MC38, and 4T1 at very low doses. Different from other IL-2 variants, SB834Fc, as single therapy, shows antitumor effect in a therapeutic injection scheme. This antitumor effect was coincident with strong stimulation of effector T cells in the spleen and in the tumor microenvironment, far above that observed with IL-2Fc, despite maintaining the same level of Treg stimulation. Additionally, induction of proliferation was demonstrated in CD8+ T cells isolated from human healthy donors, highlighting its translational value. These results support the SB834Fc fusion protein as a suitable candidate to develop a new cancer immunotherapy based in IL-2.

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来源期刊
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
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