Human interleukin 2 analogues that preferentially bind the intermediate-affinity interleukin 2 receptor lead to reduced secondary cytokine secretion : implications for the use of these interleukin 2 analogues in cancer immunotherapy

• Published in: Cancer research (Chicago, Ill.) Ill.), 1993-06, Vol.53 (11), p.2597-2602
• Main Authors: HEATON, K. M, JU, G, GRIMM, E. A
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Base Sequence; Biological and medical sciences; Humans; Immunotherapy; Interferon-gamma - secretion; Interleukin-1 - secretion; Interleukin-2 - analogs & derivatives; Interleukin-2 - metabolism; Interleukin-2 - pharmacology; Killer Cells, Lymphokine-Activated - immunology; Medical sciences; Molecular Sequence Data; Monocytes - metabolism; Pharmacology. Drug treatments; Receptors, Interleukin-2 - metabolism; RNA, Messenger - metabolism; Tumor Necrosis Factor-alpha - secretion
• ISSN: 0008-5472; 1538-7445

Cancer patients undergoing interleukin (IL)-2-based immunotherapy frequently experience dose-limiting side effects believed to be caused by the actions of such cytokines as IL-1 beta, tumor necrosis factor (TNF)-alpha and -beta, and interferon-gamma (IFN-gamma). Human peripheral blood mononuclear cells (PBMC) or monocyte-depleted peripheral blood lymphocytes were stimulated for up to 7 days by either of 2 IL-2 analogues (R38A or F42K) that bind to the intermediate-affinity IL-2 beta gamma receptor but have reduced abilities to bind the high-affinity IL-2 receptor. We previously reported that these IL-2 analogues retain the ability to generate lymphokine-activated killing by PBMC. In this study, we analyzed the cytokine content of supernatants from stimulated PBMC and peripheral blood lymphocyte cultures by enzyme-linked immunosorbent assay. The secretions of IL-1 beta, TNF-alpha, and -beta, and IFN-gamma induced by either R38A or F42K were markedly reduced compared with secretions produced in response to recombinant wild-type IL-2. In 4 experiments, secretion was reduced an average of 39% for IL-1 beta, 57% for TNF-alpha, 83% for TNF-beta, and 86% for IFN-gamma. Polymerase chain reaction analysis of recombinant wild-type IL-2 or analogue-stimulated PBMC did not reveal the presence of IL-2 mRNA; thus, differential production of endogenous IL-2 could not account for these findings. These data suggest the interaction of IL-2 and the high-affinity IL-2 receptor on human PBMC or peripheral blood lymphocyte is required for maximal secretion of IL-1 beta, TNF-alpha, TNF-beta, and IFN-gamma. Because such cytokines are believed to mediate the toxicity seen with IL-2-based immunotherapies, IL-2 analogues with reduced binding to the high affinity IL-2 receptor may prove to be an effective and less toxic means of cancer treatment.