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A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo.
- Source :
-
Nature biotechnology [Nat Biotechnol] 2000 Nov; Vol. 18 (11), pp. 1197-202. - Publication Year :
- 2000
-
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.
- Subjects :
- Animals
Antineoplastic Agents toxicity
Cell Division
Cell Separation
Dose-Response Relationship, Drug
Flow Cytometry
Humans
Interleukin-2 analogs & derivatives
Interleukin-2 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
Neoplasm Transplantation
Pan troglodytes
Protein Binding
Protein Structure, Secondary
Recombinant Proteins genetics
Recombinant Proteins therapeutic use
Recombinant Proteins toxicity
T-Lymphocytes drug effects
Temperature
Time Factors
Antineoplastic Agents therapeutic use
Interleukin-2 genetics
Interleukin-2 therapeutic use
Mutation
T-Lymphocytes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1087-0156
- Volume :
- 18
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Nature biotechnology
- Publication Type :
- Academic Journal
- Accession number :
- 11062441
- Full Text :
- https://doi.org/10.1038/81199