A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo.

Abstract	Human interleukin 2 (IL-2; Proleukin) is an approved therapeutic for advanced-stage metastatic cancer; however, its use is restricted because of severe systemic toxicity. Its function as a central mediator of T-cell activation may contribute to its efficacy for cancer therapy. However, activation of natural killer (NK) cells by therapeutically administered IL-2 may mediate toxicity. Here we have used targeted mutagenesis of human IL-2 to generate a mutein with approximately 3,000-fold in vitro selectivity for T cells over NK cells relative to wild-type IL-2. We compared the variant, termed BAY 50-4798, with human IL-2 (Proleukin) in a therapeutic dosing regimen in chimpanzees, and found that although the T-cell mobilization and activation properties of BAY 50-4798 were comparable to human IL-2, BAY 50-4798 was better tolerated in the chimpanzee. BAY 50-4798 was also shown to inhibit metastasis in a mouse tumor model. These results indicate that BAY 50-4798 may exhibit a greater therapeutic index than IL-2 in humans in the treatment of cancer and AIDS.
Authors	A B Shanafelt, Y Lin, M C Shanafelt, C P Forte, N Dubois-Stringfellow, C Carter, J A Gibbons, S L Cheng, K A Delaria, R Fleischer, J M Greve, R Gundel, K Harris, R Kelly, B Koh, Y Li, L Lantz, P Mak, L Neyer, M J Plym, S Roczniak, D Serban, J Thrift, L Tsuchiyama, M Wetzel, M Wong, A Zolotorev
Journal	Nature biotechnology (Nat Biotechnol) Vol. 18 Issue 11 Pg. 1197-202 (Nov 2000) ISSN: 1087-0156 [Print] United States
PMID	11062441 (Publication Type: Journal Article)
Chemical References	Antineoplastic Agents Interleukin-2 Recombinant Proteins aldesleukin
Topics	Animals Antineoplastic Agents (therapeutic use, toxicity) Cell Division Cell Separation Dose-Response Relationship, Drug Flow Cytometry Humans Interleukin-2 (analogs & derivatives, genetics, therapeutic use, toxicity) Kidney (drug effects) Killer Cells, Natural (metabolism) Kinetics Leukocytes, Mononuclear (metabolism) Liver (drug effects) Male Melanoma, Experimental (drug therapy) Mice Mice, Inbred C57BL Models, Molecular Mutagenesis, Site-Directed Mutation Neoplasm Transplantation Pan troglodytes Protein Binding Protein Structure, Secondary Recombinant Proteins (genetics, therapeutic use, toxicity) T-Lymphocytes (drug effects, metabolism) Temperature Time Factors

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