Identification and evaluation of potential systemic toxicity of recombinant human interleukin-2 in wistar rats based on therapeutic dosing regimen.

Recombinant human Interleukin-2 (rhIL-2) continues to be in therapeutic application for the treatment of melanoma and renal cell carcinoma. A regimen of several, repeated dose, daily intravenous injections for 14 or 28 days duration has been shown to induce mortality prior to scheduled terminal sacrifice of the animals. The conventional study design not only manifests in pre-terminal mortalities but also minimizes the characterization of toxic profile of the molecule. In humans, each intravenous treatment exposure involves two five-day treatment cycles separated by 9 days of rest period. The current 28-day study has been designed with three cycles of treatment and two rest periods, each treatment period comprising 5 days of consecutive treatment with 6 or 7 days of rest period. The study included three dose levels at 10, 20 and 40 times the human dose. Treatment related clinical signs such as reduction in the spontaneous activity of animals, abdominal breathing and scruffy coat were noticed in a few animals treated at mid- or high-dose levels. Treatment induced adverse changes were apparent in platelet counts and plasma activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (GGT) at mid- or high-dose levels. Histopathology revealed inflammatory cell infiltrates and/or its associated degenerative/regenerative changes in lung, liver and kidneys. The pharmacodynamic response, increase in white pulp was observed in the spleen, which was also evident in the total leukocyte count (WBC count) with a primary increase in the counts of lymphocytes and eosinophils. At the lowest dose level, which was 10 times the human dose, there were no manifestations of major adverse toxicity.