A novel human IL-2 mutein with minimal systemic toxicity exerts greater antitumor efficacy than wild-type IL-2.
A novel human IL-2 mutein with minimal systemic toxicity exerts greater antitumor efficacy than wild-type IL-2.
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一种具有最小全身毒性的新型人 IL-2 突变蛋白比野生型 IL-2 具有更强的抗肿瘤功效
DOI：
10.1038/s41419-018-1047-2
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发表时间：
2018-09-24
影响因子：
9
通讯作者：
Liu G
中科院分区：
文献类型：
--
作者：
Chen X;Ai X;Wu C;Wang H;Zeng G;Yang P;Liu G
IL-2对T细胞和NK细胞的活化、生长和存活至关重要，并维持自身免疫和抗肿瘤监测之间的微妙平衡。高剂量的IL-2具有明显的抗肿瘤能力，但也具有严重的副作用，限制了其临床应用。副作用包括血管渗漏综合征（VLS），导致肺水肿和肝损伤。因此，不诱导器官毒性的新型IL-2将改善基于IL-2的免疫疗法。我们通过改变IL-2与其受体IL-2 R相互作用区域的一个氨基酸来进行系统的筛选，以选择一个特定的突变体IL-2，FSD 13，其中第65位的脯氨酸被赖氨酸取代（P65 L）。FSD 13在刺激CD 4 +T、CD 8 +T和NK细胞增殖、增强这些细胞中的CD 69、CD 183、CD 44和CD 54的表达以及触发癌细胞凋亡方面具有比野生型IL-2更强的能力。FSD 13在诱导CD 4 +T细胞转化为T细胞方面比野生型IL-2低3倍。与野生型IL-2相比，FSD 13极大地限制了黑色素瘤的生长、对邻近组织的侵袭和肺转移。与野生型IL-2相反，高剂量的FSD 3不改变结构并且不诱导肝和肺中的任何致病性变化。因此，我们通过靶向与先前报道不同的区域产生了新的IL-2突变体FSD 13。FSD 13在刺激抗肿瘤免疫细胞功能方面超过野生型IL-2的能力，但产生的全身毒性要小得多。
IL-2 is critical to the activation, growth, and survival of T cells and NK cells, and maintains the delicate balance between auto-immunity and anti-neoplasm surveillance. High IL-2 doses have clear antitumor capabilities, but also have severe side effects that limit its clinical use. Side effects include the vascular leak syndrome (VLS), which results in lung edema and liver damage. Therefore, a new version of IL-2 that does not induce organ toxicity would improve IL-2-based immunotherapy. We conducted a systematic screening by changing one amino acid at a time at the interaction area of IL-2 with its receptor IL-2R to select one particular mutant IL-2, FSD13, in which the proline at position 65 was substituted by lysine (P65L). FSD13 had a greater ability than wild-type IL-2 in stimulating CD4+T, CD8+T, and NK cell proliferation, enhancing the expression of CD69, CD183, CD44, and CD54 in these cells, and triggering cancer cell apoptosis. FSD13 had three-time lower than wild-type IL-2 in inducing CD4+T to Tregs. Compared with wild-type IL-2, FSD13 greatly limited the growth, invasion into adjacent tissues, and metastasis of melanoma metastatic into the lung. In contrast to wild-type IL-2, high dose of FSD3 did not alter structures and induce any pathogenic changes in the liver and lung. Thus, we generated a novel the IL-2 mutant, FSD13, by targeting a different area than previously reported. FSD13 surpasses the wild-type IL-2’s ability in stimulating the antitumor immune cell functions, but exerts much less systemic toxicity.
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影响因子：
45.3
作者：
Cesana, GC;DeRaffele, G;Kaufman, HL
通讯作者：
Kaufman, HL
DOI：
10.1007/s00005-009-0021-1
发表时间：
2009-05-01
影响因子：
3.2
作者：
Khattar, Mithun;Chen, Wenhao;Stepkowski, Stanislaw M.
通讯作者：
Stepkowski, Stanislaw M.
影响因子：
2.4
作者：
Little, Emily G.;Eide, Melody J.
通讯作者：
Eide, Melody J.
影响因子：
82.9
作者：
Curiel, TJ;Coukos, G;Zou, WP
通讯作者：
Zou, WP
影响因子：
64.8
作者：
Tan, Wei;Zhang, Weizhou;Strasner, Amy;Grivennikov, Sergei;Cheng, Jin Q.;Hoffman, Robert M.;Karin, Michael
通讯作者：
Karin, Michael