Low-dose interleukin-2 therapy: a promising targeted therapeutic approach for systemic lupus erythematosus

Abstract

Purpose of reviewLow-dose interleukin-2 (IL-2) therapy is increasingly recognized as a promising novel therapeutic concept in inflammatory and autoimmune diseases, in particular in systemic lupus erythematosus (SLE). As IL-2 is indispensable for the growth and survival of regulatory T cells (Treg), deficiency of this regulatory cytokine plays a significant role in immune dysregulation and breach of tolerance in SLE. Recovery of Treg activity by low-dose IL-2 therapy directly interferes with the immune pathology in SLE and thus can be considered a targeted treatment approach with a unique and physiological mode of action.Recent findingsIn this review, the pathophysiological rationales behind the concept of low-dose IL-2 therapy in SLE will be explained and major advances in translational research and the clinical development of low-dose IL-2 therapy focusing on the results from two recent, randomized and placebo-controlled phase 2 trials will be highlighted.SummarySeveral clinical studies including two recent randomized trials have proven the very good safety profile of low-dose IL-2 therapy and its capability to selectively recover and expand the Treg population in patients with active SLE. Given the emerging evidence for the clinical potential of low-dose IL-2 therapy in SLE, these studies strongly confirm the pathophysiological concept behind this targeted therapeutic approach in SLE and provide a robust basis for establishing further in-depth and confirmatory clinical trials testing the application of low-dose IL-2 in SLE and other autoimmune diseases.

Molecular characterisation of lupus low disease activity state (LLDAS) and DORIS remission by whole-blood transcriptome-based pathways in a pan-European systemic lupus erythematosus cohort

“…Inflammatory and regulatory cytokine signalling pathways were herein found to be associated with active SLE, including several that previously have been coupled with SLE pathogenesis or activity 52–54. In contrast, IL-2, IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor signalling was associated with LLDAS and DORIS remission, also corroborating previous literature 55–57…”

Lupus susceptibility gene Pbx1 controls the development, stability, and function of regulatory T cells via Rtkn2 expression

“…There is strong evidence that T reg cells control the T FH cell pool, either directly or indirectly through the T FR population ( 54 ), which may be one of the mechanisms by which alterations in T reg cells contribute to SLE pathogenesis. Regardless of the mechanisms, the success of T reg cell adoptive therapy in one SLE patient ( 55 ), as well as recent clinical trials in which patients with SLE received low-dose IL-2 to expand T reg cells ( 56 ), indicates their significance as therapeutic targets.…”

Pathogenesis and novel therapeutics of regulatory T cell subsets and interleukin-2 therapy in systemic lupus erythematosus

“…There are new modified forms of IL-2 which exhibit an extended half-life or a higher affinity for trimeric IL-2R in clinical trials ( 125 ). IL-2 mutein NKTR-358 with an extended half-life between 7 and 13 days had clinical effects on skin lupus and increased the number and percentage of CD25 hi Tregs in a randomized, placebo-controlled phase 1 trial ( 121 ).…”