Preliminary pharmacokinetic evaluation of Albuleukin; an interleukin-2 human serum albumin fusion protein, in solid tumor patients

4757 Albuleukin is a novel therapeutic protein generated by the fusion of the human serum albumin and interleukin-2 genes. It was hypothesized that fusion to albumin would combine the short-acting but potent pharmacological activity of interleukin-2 and the favorable pharmacokinetic properties of albumin. Two Phase 1 clinical trials of Albuleukin are ongoing in patients with solid tumors. The objective of these studies is to determine the safety, tolerability, and pharmacokinetics of subcutaneously administered Albuleukin. In the first trial, doses of 2.0, 6.6, 22and 44 μg/kg of Albuleukin have been given every 2 weeks. In the second study, doses of 1.0, 3.3, 11 and 22 μg/kg have been administered weekly. Plasma samples for pharmacokinetic analysis were obtained at times out to one week following dosing. Plasma Albuleukin concentrations following the 1.0 μg/kg dose were below the 2 ng/mL limit of quantitation. Albuleukin was detectable in 4/5 patients given a 2.0 μg/kg dose, and in all patients at higher doses. Absorption of Albuleukin was prolonged with the Cmax occurring approximately 24-48 hours after dosing. The Cmax increased linearly with increasing dose, from a low of 6.4 ± 4.7 ng/mL after a 2.0 μg/kg dose to a high of 149 ± 76 ng/mL following a dose of 44 μg/kg. Plasma concentration curves suitable for calculation of terminal phase parameters were obtained following doses of 11, 22 and 44 μg/kg. The terminal half-life (t1/2) is 14 to 15 hours following the first SC dose of Albuleukin and is considerably longer than the reported 85-minute t1/2 for IV IL-2. The average mean residence time was between 46 and 50 hours. In most patients receiving more than one cycle of treatment, Cmax was 40-80% lower in the second and subsequent courses of Albuleukin than in the first course. Immunogenicity testing showed that subjects had not developed anti-Albuleukin antibodies that could account for the altered PK. Decreases in Cmax following multiple doses of IL-2 have been previously reported in the literature and were associated with increases in soluble IL-2 receptors. Increases in soluble IL-2 receptors have been observed following dosing with Albuleukin. The relationship between the decreased Albuleukin plasma concentrations and increased soluble IL-2 receptors will be further explored as more data become available.