Phase I trial characterizing the pharmacokinetic profile and NK and CD8+ t cell expansion with n-803, a chimeric IL-15 superagonist, in healthy volunteers.

e15008 Background: The oncotherapeutic promise of IL-15, a potent immune stimulant, is limited by short serum half-life. The fusion protein N-803 is an IL-15 superagonist complex that has > 20-fold longer half-life in vivo vs IL-15. This study characterized the pharmacokinetic (PK) profile, biological activity, and safety of N-803 after subcutaneous administration to healthy human volunteers. Methods: Volunteers were randomized 1:1 to receive 1 mg/mL or 2 mg/mL N-803. Each subject received 2 doses of N-803: 10 µg/kg followed 24 days later by 20 µg/kg. After each dose, PK and safety measures were assayed for 9 successive days. Primary endpoint was the PK profile of N-803; secondary was safety; and exploratory endpoints were cytokine levels, immune cell characterization, and immunogenicity. Results: N-803 resulted in no grade ≥3 or serious adverse events (AEs). Mild injection site reactions, chills, and pyrexia were the most common AEs. Serum N-803 concentrations peaked 10.3-15.4 hours after administration and declined with a half-life of 20.0-20.7 hours. Peak N-803 serum concentrations were dose-dependent, with a 1.5-fold increase in C max after administration of 20 µg/kg vs 10 µg/kg. In the peripheral blood, N-803 induced a transient decline, followed by a significant increase (3-fold) in NK cell number that persisted for ≥24 days. N-803 also caused a significant proliferation of NK (22-fold increase in Ki-67 + cells), CD8 + (27-fold) and CD4 + T (11-fold) cells; however, increased cell number occurred only in NK cells. N-803 administration also increased serum levels of interferon gamma, IL-10, and IL-6. One of 14 evaluable subjects had measureable anti-N-803 antibodies at the end-of-study visit. Conclusions: N-803 results in prolonged elevation of drug serum concentrations, contrasting with rapid clearance of recombinant human IL-15 (ie, half-life of ~20 vs < 1 hour). N-803 administration was well-tolerated in healthy volunteers, without evidence of adverse systemic inflammatory responses, and resulted in proliferation of NK cells and CD8 + T cells, as well as sustained increases in NK cell number. Findings in this study are consistent with published results from N-803 administration in treating liquid tumors and lung cancer. Our results demonstrate N-803 administration potentiates the proliferation and activity of lymphocytes with antitumor and antivirus properties, and suggest this investigational product holds promise in treatment of cancer as well as infectious disease such as HIV. Clinical trial information: NCT03381586 .