Therapeutic enhancement of IL-2 through molecular design

A recombinant human IL-2 analog (rIL-2, Proleukin) is currently being evaluated for clinical benefit in HIV infected patients. It is approved for therapy of patients with metastatic melanoma and renal cell carcinoma. Treatment of cancer patients with rIL-2 results in durable responses but is associated with life-threatening toxicity, which limits its use to patients in relatively good health. Antitumor efficacy associated with rIL-2 therapy are hypothesized to be mediated by distinct types of cells that express structurally different forms of the IL-2 receptor. This hypothesis suggests that it might be possible to engineer an IL-2 variant addressing the risks associated with the therapeutic use of IL-2. In this article, we review the clinical experience with IL-2 and its analogs, the evidence that different IL-2 receptors may dissociate efficacy and toxicity, and describe the generation of a novel IL-2 variant with the potential for a superior therapeutic index.