Background/Purpose: Regulatory T cell (Treg) dysfunction and impaired IL-2 production have been implicated as key immunological defects in multiple autoimmune diseases. Enhanced sensitivity of Tregs to IL-2 supports use of low-dose IL-2 therapy; however, this treatment is limited by short half-life and relatively poor selectivity for stimulation of Tregs versus other conventional T cell (Tcon) subsets and natural killer (NK) cells. NKTR-358 is a polyethylene glycol (PEG) conjugate of recombinant human IL‑2 (aldesleukin sequence with no additional amino acid mutation or substitution), and is being developed with the goal to selectively restore Treg numbers and function in autoimmune disease. NKTR-358 demonstrates prolonged biological activity as well as marked and selective stimulation of Tregs in different animal species as compared to native IL-2.

Methods: In this first-in-human, double-blind, single ascending dose study, healthy volunteers received subcutaneous doses of NKTR-358 ranging from 0.3 to 28.0 µg/kg (9 active: 3 placebo per cohort) and were followed for 50 days. The time course and extent of activation and proliferation of Tregs, Tcons, and NK cells were assessed. In addition, suppressive function of Tregs, as well as changes in gene expression and epigenetic markers in peripheral blood lymphocytes were investigated.

Results: All 8 planned cohorts completed dosing. There were no dose-limiting toxicities, serious adverse events, deaths, or clinically significant abnormalities in vital signs, electrocardiograms, or laboratory test values. The primary effect of NKTR‑358 was seen on Tregs. In the 3.0 to 28.0 µg/kg dose cohorts, dose-dependent and sustained increases in the absolute numbers, percentages, and proliferation (Ki67+) of circulating FoxP3+CD25^bright Tregs were observed. At 28.0 µg/kg, the mean peak increase in numbers of CD25^bright Tregs was 17-fold above baseline, and the mean percentage of Ki67+ CD25^bright Tregs was 6-fold above baseline. No increases in numbers of CD4+ or CD8+ Tcons were detected and the number of NK cells was increased < 4-fold at the highest dose tested. In addition to increased Treg numbers, expression of Treg activation markers ICOS and CTLA-4 increased at doses >20 μg/kg. NKTR-358-induced Tregs maintained their suppressive capacity as shown by the ability to suppress CD4+ Tcon cell proliferation in an ex vivo assay. Induction of Treg numbers was further supported by epigenetic analysis of immune cells demonstrating an increase in demethylated FOXP3. Finally, NKTR-358 administration led to dose-dependent induction of genes associated with Treg regulation, such as IDO1 and CD38.

Conclusion: In continuation of results previously reported, single ascending doses of NKTR-358 led to a dose-dependent increase in proliferation of CD25^bright Tregs. The induced Tregs displayed functional activity as evidenced by increased levels of activation markers and the capacity to suppress proliferation of Tcons. These clinical results extend previously reported effects of NKTR-358 on selective Treg stimulation and provide strong support for studying NKTR-358 as a new therapeutic in inflammatory and autoimmune diseases, such as systemic lupus.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/selective-induction-of-functional-regulatory-t-cells-in-healthy-volunteers-by-nktr-358-a-novel-il-2-conjugate-treg-stimulator-in-development-for-the-treatment-of-autoimmune-diseases/