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Receptor-gated IL-2 delivery by an anti-human IL-2 antibody activates regulatory T cells in three different species


Karakus, Ufuk; Sahin, Dilara; Mittl, Peer R E; Mooij, Petra; Koopman, Gerrit; Boyman, Onur (2020). Receptor-gated IL-2 delivery by an anti-human IL-2 antibody activates regulatory T cells in three different species. Science Translational Medicine, 12(574):eabb9283.

Abstract

Stimulation of regulatory T (Treg) 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 Treg cells and pathogenic T cells. Use of IL-2 receptor α (IL-2Rα, CD25)-biased IL-2/anti-IL-2 antibody complexes improves IL-2 selectivity for Treg 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-2Rβ (CD122) and IL-2Rγ (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+ Treg 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.

Abstract

Stimulation of regulatory T (Treg) 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 Treg cells and pathogenic T cells. Use of IL-2 receptor α (IL-2Rα, CD25)-biased IL-2/anti-IL-2 antibody complexes improves IL-2 selectivity for Treg 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-2Rβ (CD122) and IL-2Rγ (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+ Treg 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry

04 Faculty of Medicine > University Hospital Zurich > Clinic for Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > General Medicine
Language:English
Date:16 December 2020
Deposited On:27 Jan 2021 16:47
Last Modified:15 Feb 2021 14:45
Publisher:American Association for the Advancement of Science
ISSN:1946-6234
OA Status:Closed
Publisher DOI:https://doi.org/10.1126/scitranslmed.abb9283
PubMed ID:33328333

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