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

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.

Profound dysregulation of T cell homeostasis and function in patients with severe COVID‐19

“…For quantification of the main T cell subsets, blood samples were processed in the accredited routine immunology laboratory at University Hospital Zurich. Flow cytometry staining, assessment and analysis was done as established, 58,59 using the reagents and methodology detailed in the Appendix S1.…”

Crystal structure of human interleukin-2 in complex with TCB2, a new antibody-drug candidate with antitumor activity

“…The second group of antibodies is used to amplify the immune suppressive function of IL-2 by activating T reg cells. 18 JES6-1, 13 UFKA-20, 19 and 5344 18 (anti-hIL-2 antibody, BD biosciences) are good examples. JES6-1 antibody blocks IL-2Rβ binding site and left IL-2Rα binding site as accessible, therefore JES6-1 antibody complexed mouse IL-2 can bind to IL-2Rα on immunosuppressive T cells, and then JES6-1 antibody is released from IL-2 to allow IL-2 interaction with IL-2Rβ and IL-2Rγ for activation of IL-2 signaling.…”

Emerging Therapeutics for Immune Tolerance: Tolerogenic Vaccines, T cell Therapy, and IL-2 Therapy

“…These include PEGylated IL-2 (NKTR-358 "LY3471851") (303), which induced clinical response and dose-dependent changes in Treg functional markers in a phase I trial in mild-to-moderate SLE, various IL-2:IL-2 Ab complexes described as CD25-directed IL-2cx (283,284) and CD25-IL2 fusion proteins (287,288). Anti-IL-2 antibodies that form complex with IL-2 can attenuate the IL2R signal by sterically inhibiting the IL-2: IL2R interactions but they can also modify the IL-2 structure to influence the bias with which it interacts with the receptor subunits (285,286). Likewise, CD25-IL-2 fusion proteins formed multimers via intermolecular binding, effectively limiting the amount of free IL-2 that could bind to CD25 on cell surfaces.…”