利用免疫球蛋白Fc片段融合技术构建白细胞介素-2长效“超强”和“超弱”激动剂

Interleukin-2 (IL-2) has been approved as an immuno-stimulant to treat cancer for more than 20 years. The recently discovered immuno-suppressing activity of IL-2 at low concentration not only expanded its clinical usage, but also questioned its current regime. Ideal formulations of IL-2 should have both better distinguishability between its immuno-stimulating and immuno-suppressing activities and longer in vivo half-life. The development of immunoglobulin Fc fusion technology enables the re-engineering the specificity and half-life IL-2 simultaneously. In this study, we will construct homo-dimeric IL-2 and Fc and hetero-dimeric IL-2, IL-2 receptor and Fc fusion proteins. When compared to IL-2, these fusion proteins will have improved receptor affinity or dependence, which may translate into better distinguishability between its immuno-stimulating and immuno-suppressing activities. Moreover, because of the long circulating half-life of Fc, these fusion proteins will be long-acting formulations of IL-2. The improvement of the specificity and half-life of IL-2 will not only increase its drugability, but also have important implications for the development of other cytokines.

白细胞介素-2（Interleukin-2，IL-2）作为免疫刺激剂用来治疗肿瘤已有超过20年的历史。最近发现的低浓度IL-2免疫抑制活性既扩展了其潜在的临床应用前景，又揭示了现有的临床治疗方案存在的缺陷。理想的IL-2新型制剂一方面应该对其免疫刺激和免疫抑制活性具有更高的区分度，另一方面应该具有更长的半衰期。免疫球蛋白Fc片段融合技术的发展为同时对IL-2的特异性和半衰期进行改造提供了可能性。在本研究中，我们将构建IL-2和Fc片段的同源二聚体融合蛋白以及IL-2及其受体与Fc片段的异源二聚体融合蛋白。与天然IL-2相比，上述融合蛋白将具有不同的受体亲和力和依赖性，从而使其免疫刺激和免疫抑制活性具有更好的区分度。同时，由于Fc片段的长效化作用，融合蛋白的体内活性也更为持久。对IL-2的特异性和半衰期进行改造不但可以提高其成药性，而且对其它细胞因子的改造也具有重要的借鉴意义。