Abstract
Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel cytokine, created by the fusion of circularly permuted interleukin-2 (IL-2) to the IL-2Rα subunit of the IL-2 receptor (IL-2R) complex, that confers selectivity for the intermediate-affinity IL-2R expressed on CD8+ T cells and natural killer (NK) cells. The pharmacokinetics and selective pharmacodynamic properties of nemvaleukin have been demonstrated using in vitro and in vivo mouse models. The pharmacokinetic/pharmacodynamic effects of nemvaleukin on immune cell subtypes were evaluated in cynomolgus monkeys following intravenous (i.v.) and subcutaneous (s.c.) administration to inform dose selection and predict pharmacodynamic effects in humans. Male drug-naïve cynomolgus monkeys (N = 15) were administered either single-dose (i.v. 0.3 mg/kg; s.c. 0.3 mg/kg or 1.0 mg/kg) or repeated-doses (i.v. 0.1 mg/kg on days 1-5 or s.c. 0.5 mg/kg on days 1 and 4) of nemvaleukin. Serial blood samples were collected for pharmacokinetic assessment, immunophenotyping by flow cytometry, and profiling of serum cytokines. Repeat-dose s.c. administration of nemvaleukin with less frequent dosing resulted in total systemic exposure and trough serum concentrations comparable to those seen with i.v. administration, with lower peak serum concentrations. Transient elevation of interferon-γ and IL-6 peaked at 2 and 8 hours after i.v. and s.c. administration, respectively. Selective expansion of immunoprotective central memory, effector memory, and terminal effector CD8+ T cells and CD56+ NK cells, and minimal expansion of immunosuppressive CD4+CD25+FoxP3+ regulatory T cells was observed following both i.v. and s.c. administration. These data support the ongoing clinical evaluation of i.v. and s.c. nemvaleukin.
Significance Statement Administration of the novel interleukin-2 receptor agonist nemvaleukin alfa (nemvaleukin, ALKS 4230) to cynomolgus monkeys resulted in selective expansion of immune effector cells, including CD8+ T and NK cells, with minimal effects on immunosuppressive CD4+ regulatory T cells, confirming the design of nemvaleukin and highlighting its potential as a cancer immunotherapy. Subcutaneous administration of nemvaleukin achieved systemic exposure and immunostimulatory effects similar to those observed following more frequent intravenous dosing and may represent a practical alternative in a clinical setting.
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