Receptor-gated IL-2 delivery by an anti-human IL-2 antibody activates regulatory T cells in three different species
Receptor-gated IL-2 delivery by an anti-human IL-2 antibody activates regulatory T cells in three different species
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DOI：
10.1126/scitranslmed.abb9283
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发表时间：
2020-12-16
影响因子：
17.1
通讯作者：
Boyman, Onur
中科院分区：
文献类型：
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作者：
Karakus, Ufuk;Sahin, Dilara;Boyman, Onur
刺激调节性T细胞（T-reg）对治疗自身免疫、慢性炎症和某些代谢疾病有很大的希望。最近用低剂量白细胞介素-2 （IL-2）扩增Treg细胞的临床试验在自身免疫中取得了有益的结果，但IL-2免疫治疗可以激活T-reg细胞和致病性T细胞。使用IL-2受体α (IL-2R α, CD25)偏倚的IL-2/抗IL-2抗体复合物提高IL-2对T-reg细胞的选择性；然而，这类IL-2复合物的作用机制尚不完全清楚，因此阻碍了它们转化为临床试验。使用基于细胞的动态IL-2R平台，我们鉴定了一种特殊的抗人IL-2抗体，称为UFKA-20。当与UFKA-20结合时，IL-2不能刺激表达IL-2R β (CD122)和IL-2R γ (CD132)的细胞，除非这些细胞也表达大量的CD25。CD25允许IL-2/UFKA-20复合物结合，并且在CD122和CD132存在的情况下与CD25结合，随后UFKA-20与IL-2快速解离，将IL-2递送到CD122和CD132，以及细胞内信号传导。IL-2/UFKA-20复合物在离体、小鼠和恒河猴体内有效和优先刺激新分离的人T细胞CD4(+) T- regg细胞。IL-2/UFKA-20复合物的晶体结构表明，UFKA-20干扰IL-2与CD122的结合，并在较小程度上干扰CD25。我们共同将cd25偏倚的IL-2复合物从小鼠翻译到非人灵长类动物，并扩展了我们对cd25偏倚的抗人IL-2抗体如何起作用的机制理解，这为cd25偏倚的IL-2复合物的临床试验铺平了道路。
Stimulation of regulatory T (T-reg) cells holds great promise for the treatment of autoimmune, chronic inflammatory, and certain metabolic diseases. Recent clinical trials with low-dose interleukin-2 (IL-2) to expand Treg cells led to beneficial results in autoimmunity, but IL-2 immunotherapy can activate both T-reg cells and pathogenic T cells. Use of IL-2 receptor alpha (IL-2R alpha, CD25)-biased IL-2/anti-IL-2 antibody complexes improves IL-2 selectivity for T-reg cells; however, the mechanism of action of such IL-2 complexes is incompletely understood, thus hampering their translation into clinical trials. Using a cell-based and dynamic IL-2R platform, we identified a particular anti-human IL-2 antibody, termed UFKA-20. When bound to UFKA-20, IL-2 failed to stimulate cells expressing IL-2R beta (CD122) and IL-2R gamma (CD132), unless these cells also expressed high amounts of CD25. CD25 allowed IL-2/UFKA-20 complexes to bind, and binding to CD25 in the presence of CD122 and CD132 was followed by rapid dissociation of UFKA-20 from IL-2, delivery of IL-2 to CD122 and CD132, and intracellular signaling. IL-2/UFKA-20 complexes efficiently and preferentially stimulated CD4(+) T-reg cells in freshly isolated human T cells ex vivo and in mice and rhesus macaques in vivo. The crystal structure of the IL-2/UFKA-20 complex demonstrated that UFKA-20 interfered with IL-2 binding to CD122 and, to a lesser extent, also CD25. Together, we translated CD25-biased IL-2 complexes from mice to nonhuman primates and extended our mechanistic understanding of how CD25-biasing anti-human IL-2 antibodies work, which paves the way to clinical trials of CD25-biased IL-2 complexes.