Selective expansion of regulatory T cells by NKTR-358 in healthy volunteers and patients with systemic lupus erythematosus

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.

Keywords: Autoimmune disease; IL-2 receptor; Interleukin-2; Regulatory T cells; Systemic lupus erythematosus.

Fig. 1

Mean concentration–time profiles of NKTR-358 across dose cohorts after A) a single dose in the SAD study in healthy volunteers and B) biweekly multiple doses in the MAD study in patients with SLE. Abbreviations: MAD: multiple ascending dose; SAD: single ascending dose; SEM: standard error of the mean.

Fig. 2

Changes from baseline in the numbers and percentages of Tregs in peripheral blood after a single dose of NKTR-358 in the SAD study and after multiple doses of NKTR-358 in the MAD study. A) absolute number of CD25^bright Tregs; B) percentage of CD25^bright Tregs in total CD4⁺ T cells; C) fold-change in the absolute number of CD25^bright Tregs; D) fold-change in percentage of CD25^bright Tregs in total CD4⁺ T cells; E) peak level of post-baseline CD25^bright Tregs after 1 dose of NKTR-358. Abbreviations: MAD: multiple ascending dose: SAD, single ascending dose: SEM, standard error of the mean.

Fig. 3

Mean (SE) changes in absolute number of Tcon and NK cells in peripheral blood after a single dose of NKTR-358 in the SAD study and with multiple doses of NKTR-358 in the MAD study. A) CD4⁺ T cells; B) CD8⁺ T cells; C) total CD56⁺ NK cells; D) total CD56⁺ NK cells from individual SLE patients given the highest dose (24 μg/kg). Abbreviations: MAD: multiple ascending dose; NK: natural killer; SAD: single ascending dose; SEM: standard error of the mean; Tcons: conventional T cells.