Background: IL-2 analogs have a potentially important role as immune enhancers in the treatment of HIV, but are associated with significant systemic toxicity; the maximum tolerated dose (MTD) of subcutaneous (SC) aldesleukin in HIV patients (pts) is approximately 13 μg/kg/day. This study investigated the safety and pharmacokinetics of SC BAY 50-4798, a new selective recombinant IL-2 (rIL-2) agonist in cynomolgus monkeys.

Methods: BAY 50-4798 or vehicle was administered SC bid during two 5-day treatment cycles, separated by a 28-day treatment-free period. Eighty (80) cynomolgus monkeys were randomly assigned to 1 of 4 doses: 0, 8, 32, or 96 μg/kg/day. Vital signs, food consumption, biochemical parameters, and physical assessments were evaluated. Three (3) animals were euthanized after each 5-day treatment period and 2 after each subsequent recovery period. All animals were subjected to a full post-mortem.

Results: All doses were well tolerated. There were no deaths or treatment-related effects on body weight, body temperature, heart rate, respiratory rate, electrocardiogram, or urinalysis. No hypersensitivity or allergic reactions were observed. Antibodies to BAY 50-4798 were present in only 4 animals (2 at 8 µg/kg/day and 2 at 96 µg/kg/day), and there was no neutralizing antibody formation. Serum albumin values remained within the normal range at all dose levels. There were minimal injection-site reactions across the 4 groups. Diarrhea, dehydration, and decreased activity were only observed at the 96 μg/kg/day dose and resolved during the recovery periods; there were no differences in the incidence of diarrhea and dehydration between cycles. Absolute lymphocyte count increased with statistical significance (p < 0.05) after the 32 and 96 μg/kg/day doses, indicating immunological activity. Pharmacokinetics were dose-proportional. Mean pharmacokinetic half-life ranged from 1.9–2.2 hours.

Conclusions: In this primate study of a rIL-2, SC injections of BAY 50-4798 resulted in immunological activity and were well tolerated at all doses from 8 to 96 μg/kg/day. No hypersensitivity or allergic reactions were observed. The MTD of SC BAY 50-4798 given bid to cynomolgus monkeys is approximately 7 times the MTD of SC administered aldesleukin in humans. Based on these encouraging data, studies of BAY 50-4798 in HIV-infected pts are warranted.