Phase I Trial Characterizing the Pharmacokinetic Profile of N-803, a Chimeric IL-15 Superagonist, in Healthy Volunteers

Abstract

The oncotherapeutic promise of IL-15, a potent immunostimulant, is limited by a short serum t 1/2 . The fusion protein N-803 is a chimeric IL-15 superagonist that has a >20-fold longer in vivo t 1/2 versus IL-15. This phase 1 study characterized the pharmacokinetic (PK) profile and safety of N-803 after s.c. administration to healthy human volunteers. Volunteers received two doses of N-803, and after each dose, PK and safety were assessed for 9 d. The primary endpoint was the N-803 PK profile, the secondary endpoint was safety, and immune cell levels and immunogenicity were measures of interest. Serum N-803 concentrations peaked 4 h after administration and declined with a t 1/2 of ~20 h. N-803 did not cause treatment-emergent serious adverse events (AEs) or grade $3 AEs. Injection site reactions, chills, and pyrexia were the most common AEs. Administration of N-803 was well tolerated and accompanied by proliferation of NK cells and CD8 + T cells and sustained increases in the number of NK cells. Our results suggest that N-803 administration can potentiate antitumor immunity.

ALT-803 in the treatment of non-muscle-invasive bladder cancer: Preclinical and clinical evidence and translational potential

“…ALT-803 concentration easily induces fever and tachycardia compared with S.C. administration. The PK profiles and safety of ALT-803 in healthy human volunteers were similar to those in patients with cancer ( 28 ). Therefore, S.C. administration is preferable.…”

“…S.C. ALT-803 promotes the serum IFN-γ, IL-6, and IL-10 levels but does not change the TNFα, IL-4, and IL-2 levels in these healthy volunteers. The immunological effect of S.C. ALT-803 in healthy human volunteers is similar to that observed in patients with cancer, suggesting that S.C. ALT-803 may have the potential to inhibit cancer development ( 28 ). However, more studies are needed to confirm this view.…”

“…Indeed ALT-803’s concentration remained above baseline at 3 days after a single S.C. dose and promoted the number of NK cells for at least 15 days. The half-life of S.C. ALT-803 is approximately 20 h, and its half-life and tissue exposure are, respectively, 20- and 2.3-fold higher than that of rhIL-15 ( 28 ), suggesting that the efficacy of ALT-803 is higher than that of rhIL-15 in humans. The serum ALT-803 levels peaked 4 h after S.C. ALT-803 in healthy human volunteers.…”

“…administration in the clinical trial (NCT01885897), suggesting that S.C. administration may be more advantageous than I.V. administration ( 28 ).…”

From CD16a Biology to Antibody-Dependent Cell-Mediated Cytotoxicity Improvement

“…It did not produce adverse events and persisted in circulation ~10-fold longer as compared to IL-15. Moreover, it increased NK and CD8 T-cell numbers (92). N-803 has been used instead of IL-2 to support cytokine-primed allogeneic NK cells transfer to AML patients in a relapse in two separate clinical trials (NCT03050216 and NCT01898793).…”