Abstract
OBJECTIVE: To evaluate NKTR-358, a polyethylene glycol-interleukin-2 conjugate composition designed to selectively induce regulatory T cells (Tregs), in first-in-human studies. METHODS: Healthy volunteers and patients with systemic lupus erythematosus (SLE) received single- or multiple-dose (biweekly) NKTR-358 or placebo in two sequential, randomized, phase 1 studies (single ascending dose [SAD; NCT04133116] and multiple ascending dose [MAD; NCT03556007]). Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics (PK) and immune effects of NKTR-358; exploratory objectives included effects on SLE disease activity. RESULTS: There were eight ascending dose cohorts in the SAD study (0.3-28.0 μg/kg: n = 76; placebo: n = 24) and four in the MAD study (3-24.0 μg/kg: n = 36; placebo: n = 12). Most adverse events (AEs) were grade 1-2 injection-site reactions, with no treatment-related serious or severe AEs, or deaths. PK data showed dose proportionality and prolonged exposure (mean half-life: 7.4-12.9 days). Dose-dependent, selective, and sustained increases in percentages and absolute numbers of total CD4(+) Tregs and CD25(bright) Tregs were observed, with no significant changes in conventional CD4(+) and CD8(+) T cells, and low-level increases in natural killer cells. At the highest doses tested, administration of NKTR-358 resulted in a 12-17-fold increase in CD25(bright) Tregs over baseline that was sustained for 20-30 days. CONCLUSION: NKTR-358 was well tolerated, had a suitable PK profile for biweekly dosing, and led to marked and selective dose-dependent increases in CD25(bright) Tregs, with no significant changes in conventional T cells. These results provide strong support for further testing in SLE and other inflammatory diseases.