Background AMG 592 is an investigational IL-2 mutein designed for greater regulatory T-cell (Treg) selectivity and longer half-life than recombinant IL-2 (aldesleukin). We investigated the tolerability of AMG 592 and its effects on expansion of Tregs, conventional effector T-cells (Tcon), and natural killer (NK) cells.

Methods AMG 592 activity, in comparison with aldesleukin, was assessed by in vitro phosphorylated STAT5 (pSTAT5), Treg/Tcon/NK cell expansion, and cytokine production in primary human peripheral blood mononuclear cells (hPBMC). Effects on body temperature (Temp), C-reactive protein (CRP), and peripheral Treg/Tcon/NK cell numbers were evaluated in cynomolgus monkeys (CM). In an FIH study, healthy volunteers received single ascending SC AMG 592 doses (n=6/dose; 8 cohorts) or placebo (n=2/dose) for 28 days. Adverse events (AEs), pharmacokinetics (PK), pharmacodynamics, and cytokines were evaluated.

Results In hPBMC cultures, AMG 592 caused more selective Treg response (pSTAT5, proliferation) and lower proinflammatory cytokine levels than aldesleukin. Dose-dependent expansion of FoxP3 +Tregs was associated with increased Temp and CRP in aldesleukin-treated but not in AMG 592-treated CM. In the FIH study, AMG 592 was well tolerated, with no serious AEs. The most common AE across cohorts was grade 1 painless erythema at/near the injection site which resolved without treatment. Preliminary PK results indicate dose-related increases in AMG 592 serum exposure. AMG 592 caused robust, dose-dependent Treg expansion relative to Tcon in all treated individuals. Expanded Tregs had increased CD25 and FoxP3, and were enriched for recent thymic emigrants. At the highest dose, increase in Treg: Tcon ratio peaked at day 8 (~4 fold vs baseline) and remained elevated up to day 29. AMG 592-mediated Treg expansion was highly selective, with no directional change in NK cell numbers and minimal increase in Tcon; there were no increases in serum proinflammatory cytokines IL-6, TNFα, or IFN-γ above the limits of detection.

Conclusion AMG 592 caused dose-dependent, selective Treg expansion in healthy volunteers. Lack of proinflammatory cytokines and reduced inflammation markers suggest a wider therapeutic margin, and sustained Treg elevation implies less frequent dosing, compared with aldesleukin. Further investigation of AMG 592-induced Treg-mediated restoration of immune homeostasis in inflammatory and autoimmune diseases is warranted.