Reduced secondary cytokine induction by BAY 50-4798, a high-affinity receptor-specific interleukin-2 analog

• Published in: Journal of interferon & cytokine research Vol. 26; no. 3; pp. 171 - 178
• Main Authors: Steppan, Sonja, Eckart, Michael R, Bajsarowicz, Krystyna, Sternberg, Lawrence R, Greve, Jeffrey M, Cassell, Delanie J
• Format: Journal Article
• Language: English
• Published: United States Mary Ann Liebert, Inc 01.03.2006
• Subjects: Cell Proliferation - drug effects; Cells, Cultured; Chemistry, Pharmaceutical; Concanavalin A - pharmacology; Cytokines - biosynthesis; Dose-Response Relationship, Drug; Human immunodeficiency virus; Humans; Interleukin-2 - analogs & derivatives; Interleukin-2 - pharmacology; Killer Cells, Natural - cytology; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Kinetics; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Mitogens - pharmacology; Receptors, Interleukin-2 - metabolism; Recombinant Proteins - pharmacology; RNA, Messenger - analysis; Transcription, Genetic - drug effects
• ISSN: 1079-9907; 1557-7465
• DOI: 10.1089/jir.2006.26.171

Recombinant interleukin-2 (IL-2) (aldesleukin, Proleukin, Chiron, Emeryville, CA) is approved for treatment of cancer patients and under investigation in HIV-infected individuals. However, treatment with aldesleukin is associated with toxicity, which may be due to its elicitation of inflammatory mediators from cells that express the intermediate-affinity IL-2 receptor. BAY 50-4798, a novel IL-2 analog, is a selective agonist for the high-affinity receptor. It induces the proliferation of activated T cells with a potency similar to that of aldesleukin but has reduced activity on cells expressing the intermediate-affinity receptor. In the current study, we compared cytokine responses elicited in peripheral blood mononuclear cell (PBMC) cultures stimulated with BAY 50-4798 or aldesleukin. BAY 50-4798 induced approximately 5-fold lower mean levels of endogenous IL-2 than aldesleukin, and at least 50% lower levels of proinflammatory cytokines, such as tumor necrosis fctor-alpha (TNF-alpha), IL-1beta, IL-6, and interferon-gamma (IFN-gamma). Furthermore, statistically significant reductions in the levels of IL-5, IL-8, IL-10, IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were observed in response to BAY 50-4798. These findings increase our understanding of the biologic action of BAY 50-4798 and suggest a mechanism by which it may exhibit better safety than aldesleukin in humans.