Interleukin-2 (IL-2) is a hormone of the immune system responsible for control of the proliferation and cytotoxicity of T lymphocytes and natural killer cells as well as the proliferation of B lymphocytes. Recombinant IL-2 has been only minimally to modestly successfully to date in the treatment of cancer and infectious diseases, largely because the drug is associated with toxicity and a narrow therapeutic index. Quantitative measurement of IL-2 can be quickly done by enzyme immunoassay. IL-2 bioassay provides an index of biologically active cytokine. IL-2 action and pharmacokinetics can be understood in the context of the effect IL-2 on high (alpha, beta, gamma trimer) vs intermediate (alpha, beta) vs low (beta only or alpha only) affinity IL-2 receptors on various cells of the immune system. IL-2 undergoes rapid renal elimination. The route of administration is important to determine the provision of sustained drug concentrations adequate to support the proliferation and cytotoxicity of immune cells. When IL-2 is given intravenously it has rapid elimination pharmacokinetics with an initial elimination half-life and terminal elimination half-life (t1/2 beta) of 6 to 12 minutes and 40 to 80 minutes, respectively. Subcutaneous or intramuscular administration of IL-2 results in sustained systemic absorption and approximately 30% of the injected dose is absorbed. Because IL-2 is less rapidly cleared from the site of intracavitary injection, when the drug is given by these less traditional routes (e.g. intraperitoneal, intrapleural, intrathecal, intraventricular, intravesicular, and inhalational administration) sustained local IL-2 activity can result. In some cases this has resulted in an improved therapeutic index compared with that resulting after administration of the drug by high dose intravenous bolus or continuous infusion. Depot IL-2 preparations may offer more convenient administration (e.g. t1/2 beta of polyethylene glycolated IL-2 is approximately 10-fold higher than that of recombinant IL-2) or more favourable biodistribution (e.g. IL-2 liposomes are more potent against lung metastases) compared with IL-2 administered by more conventional routes. An understanding of IL-2 clinical pharmacokinetics in relation to immunobiology of this central cytokine should lead to less toxicity and more effective clinical use.

Undesirable toxic effects associated with intravenous interleukin-2 (IL2) therapy have limited its use for the treatment of cancer. Therefore, we investigated properties of a colloidal carrier system intended for the delivery of IL2. Lipid microspheres (LMS) are 10% (v/v) soybean oil emulsions stabilized with block copolymers of the poloxamer and poloxamine type. Poloxamers 238,338,407 or poloxamine 908 LMS were evaluated for physical stability, in uitro toxicity, and in viuo biodistribution. With the exception of 2% poloxamer 238 LMS, all preparations displayed acceptable stability when stored for 3 months at 4" or 37°C. In addition, all LMS preparations exhibited physical stability when subjected to freezethaw cycling and extended periods of freezing. In uitro cellular toxicity was evaluated in a murine cytotoxic T lymphocyte cell line (CTLL-2) and human peripheral blood mononuclear cells (PBMC). The calculated ICs0 of LMS was approximately 30 and 10 mg/liter in CTLL-2 cells and PBMC, respectively. Biodistribution studies involving 12sI-labeled LMS revealed that 2 h after intravenous administration there was significantly greater recovery of the poloxamer 338 and 407 LMSassociated radioactivity, where blood, liver, spleen, and bone marrow accounted for most of the radioactivity. Overall, the data suggest that LMS have the potential to serve as a drug delivery system. o

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