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
- ALKS 4230: a novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy.
- Authors: Lopes JE, Fisher JL, Flick HL, Wang C, Sun L, Ernstoff MS, Alvarez JC, Losey HC
- Issue date: 2020 Apr
- Discovery of a novel IL-15 based protein with improved developability and efficacy for cancer immunotherapy.
- Authors: Hu Q, Ye X, Qu X, Cui D, Zhang L, Xu Z, Wan H, Zhang L, Tao W
- Issue date: 2018 May 16
- A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo.
- Authors: Shanafelt AB, Lin Y, Shanafelt MC, Forte CP, Dubois-Stringfellow N, Carter C, Gibbons JA, Cheng SL, Delaria KA, Fleischer R, Greve JM, Gundel R, Harris K, Kelly R, Koh B, Li Y, Lantz L, Mak P, Neyer L, Plym MJ, Roczniak S, Serban D, Thrift J, Tsuchiyama L, Wetzel M, Wong M, Zolotorev A
- Issue date: 2000 Nov
- 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
- Role of effector cell-derived IL-4, IL-5, and perforin in early and late stages of type 2 CD8 effector cell-mediated tumor rejection.
- Authors: Dobrzanski MJ, Reome JB, Dutton RW
- Issue date: 2001 Jul 1