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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 Immunotherapy¹

Departments of Tumor Biology and General Surgery, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [K. M. H., E. A. G.], and the Department of Inflammation/Autoimmune Diseases, Hoffmann-LaRoche, Inc., Nutley, New Jersey 07110 [G. J.]

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-1ß, tumor necrosis factor (TNF)- and -ß, and interferon- (IFN-). 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-2ß 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-1ß, TNF-, and -ß, and IFN- 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-1ß, 57% for TNF-, 83% for TNF-ß, and 86% for IFN-. 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-1ß, TNF-, TNF-ß, and IFN-. 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.

¹ Supported by NIH Grant CA45445 (E. A. G.), National Cancer Institute General Surgery Training Grant 5 T32 CA09500-04 (K. M. H.), and Core Grant CA 16672.

² To whom requests for reprints should be addressed, at the Department of Tumor Biology, Box 79, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.

Received 1/18/93. Accepted 3/22/93.

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