A novel human IL-2 mutein with minimal systemic toxicity exerts greater antitumor efficacy than wild-type IL-2
JournalCell Death and Disease
PublisherNature Publishing Group
MetadataShow full item record
AbstractIL-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. Copyright 2018, The Author(s).
SponsorsThis work was supported in part by grants from the National Natural Science Foundation of China (Numbers 81272433, 81328018, 81372300, 81472732 and 8177315).
KeywordAmino Acid Sequence--genetics
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85053807747&doi=10.1038%2fs41419-018-1047-2&partnerID=40&md5=c0c4b174eaaf73f077042d924203cef7; http://hdl.handle.net/10713/9215
- Human IL-2 mutein with higher antitumor efficacy than wild type IL-2.
- Authors: Carmenate T, Pacios A, Enamorado M, Moreno E, Garcia-Martínez K, Fuente D, León K
- Issue date: 2013 Jun 15
- Melittin-MIL-2 fusion protein as a candidate for cancer immunotherapy.
- Authors: Liu M, Wang H, Liu L, Wang B, Sun G
- Issue date: 2016 Jun 1
- Interleukin-2: Old and New Approaches to Enhance Immune-Therapeutic Efficacy.
- Authors: Dhupkar P, Gordon N
- Issue date: 2017
- Cellular immunotherapy using irradiated lung cancer cell vaccine co-expressing GM-CSF and IL-18 can induce significant antitumor effects.
- Authors: Tian H, Shi G, Yang G, Zhang J, Li Y, Du T, Wang J, Xu F, Cheng L, Zhang X, Dai L, Chen X, Zhang S, Yang Y, Yu D, Wei Y, Deng H
- Issue date: 2014 Jan 29
- Tumoral expression of IL-33 inhibits tumor growth and modifies the tumor microenvironment through CD8+ T and NK cells.
- Authors: Gao X, Wang X, Yang Q, Zhao X, Wen W, Li G, Lu J, Qin W, Qi Y, Xie F, Jiang J, Wu C, Zhang X, Chen X, Turnquist H, Zhu Y, Lu B
- Issue date: 2015 Jan 1