Background/Purpose: Treg dysfunction and impaired IL-2 production have been implicated as key immunological defects in the breakdown of immune self-tolerance in SLE. Low-dose IL-2 can expand Tregs, but this therapy has a narrow therapeutic window for stimulation of Tregs versus conventional T cells (Tcons), and a short half-life. NKTR-358, a polyethylene glycol (PEG) conjugate of recombinant human IL‑2 (aldesleukin sequence), has altered IL-2 receptor binding and prolonged biological activity compared with native IL-2. In healthy volunteers, single SC administration led to a dose-dependent increase in Tregs with no elevation of Tcons.

Methods: In this double-blind, multiple ascending dose, Phase 1b study (NCT03556007), 48 patients with mild to moderate SLE activity (per ACR criteria) received 3 SC doses q2w of NKTR-358 in 4 cohorts ranging from 3 to 24 µg/kg (9 active: 3 placebo per cohort) and were followed for 50 days after the last dose. The time course and extent of activation and proliferation of peripheral blood Tregs, Tcons, and NK cells were assessed. Changes in gene expression and epigenetic markers were also investigated.

Results: There were no dose-limiting toxicities, deaths, or clinically significant abnormalities in vital signs or electrocardiograms. Adverse events attributed to NKTR-358 were primarily limited to mild (grade 1 or 2) injection site reactions. Dosing was stopped in 1 subject due to elevated eosinophil levels, without clinical sequelae. NKTR-358 demonstrated dose-dependent numerical improvements in the Cutaneous Lupus Erythematosus Disease Area and Severity Index score; however, the small number of patients per dose, low entry disease activity, and short treatment duration limited comprehensive assessment of disease activity.
The primary effect of NKTR‑358 was seen on Tregs.  In the 3 to 24 µg/kg cohorts, dose-dependent, sustained increases in absolute number, percentage, and proliferation (Ki67+) of circulating FoxP3+CD25^bright Tregs were observed, with levels remaining elevated throughout the dosing period. At 24 µg/kg, the maximum mean peak increase in number of CD25^bright Tregs was 12-fold above baseline and the maximum mean percentage of Ki67+ CD25^bright Tregs was 5-fold above baseline, not returning to predose levels until 20–30 days after the last dose. No increases in CD4+ or CD8+ Tcon numbers were detected, and low-level increases in the percentage of NK cells were noted at the highest dose tested. Induction of Tregs was further supported by a correlation of number of Tregs identified by flow cytometry and extent of demethylated FoxP3 at ≥12 µg/kg. Expression of Treg activation markers CD25, Helios, and CTLA4 were induced at ≥12 µg/kg, and NKTR-358 also led to dose-dependent induction of genes associated with Treg regulation, such as IDO1.

Conclusion: These results extend findings previously reported in healthy volunteers. In the current study in patients with SLE, NKTR-358 was safe and well tolerated, and led to a sustained and selective dose-dependent increase in CD25^bright Tregs. Induced Tregs displayed increased levels of activation markers. Together, these data provide strong support for continued development of NKTR-358 in patients with SLE as well as in other inflammatory diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/selective-expansion-of-regulatory-t-cells-in-patients-with-systemic-lupus-erythematosus-by-a-novel-il-2-conjugate-nktr-358/