Reduced secondary cytokine induction by BAY 50-4798, a high-affinity receptor-specific interleukin-2 analog.
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.
Steppan
Sonja
S
Biotechnology Research Division, Bayer Corporation, Berkeley, CA 94710, USA. Sonja_Steppan@gmail.com
Eckart
Michael R
MR
Bajsarowicz
Krystyna
K
Sternberg
Lawrence R
LR
Greve
Jeffrey M
JM
Cassell
Delanie J
DJ
D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007376:Interleukin-2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D016207:Cytokines; D007376:Interleukin-2; D008934:Mitogens; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D003208:Concanavalin A; C082598:aldesleukin