6ye3
From Proteopedia
IL-2 in complex with a Fab fragment from UFKA-20
Structural highlights
DiseaseIL2_HUMAN Note=A chromosomal aberration involving IL2 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(4;16)(q26;p13) with involves TNFRSF17. FunctionIL2_HUMAN Produced by T-cells in response to antigenic or mitogenic stimulation, this protein is required for T-cell proliferation and other activities crucial to regulation of the immune response. Can stimulate B-cells, monocytes, lymphokine-activated killer cells, natural killer cells, and glioma cells. Publication Abstract from PubMedStimulation 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 T(reg) 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-2Ralpha, 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-2Rbeta (CD122) and IL-2Rgamma (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. Receptor-gated IL-2 delivery by an anti-human IL-2 antibody activates regulatory T cells in three different species.,Karakus U, Sahin D, Mittl PRE, Mooij P, Koopman G, Boyman O Sci Transl Med. 2020 Dec 16;12(574):eabb9283. doi: 10.1126/scitranslmed.abb9283. PMID:33328333[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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