A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo
| Autor: | Marie-Claude Shanafelt, Jacqueline A. Gibbons, Monte Wetzel, Lauri Neyer, Yue Lin, Alya Zolotorev, Mary Jane Plym, Shu-lan Cheng, Beth Koh, John Thrift, Armen B. Shanafelt, Robert Gundel, Nathalie A. Dubois-Stringfellow, Richard Fleischer, Linda Tsuchiyama, Carla P. Forte, Daniel Serban, Ruth Kelly, Katherine A. Delaria, Steve Roczniak, Ying Li, Polly Mak, Christopher A. Carter, Lori Lantz, Harris Kathleen, Mel Wong, Jeffrey M. Greve |
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| Rok vydání: | 2000 |
| Předmět: |
Interleukin 2
Male Models Molecular Time Factors Pan troglodytes medicine.medical_treatment T cell T-Lymphocytes Biomedical Engineering Melanoma Experimental Bioengineering Antineoplastic Agents Cell Separation Pharmacology Biology Kidney Applied Microbiology and Biotechnology Protein Structure Secondary Natural killer cell Metastasis Mice Therapeutic index In vivo medicine Animals Humans Dose-Response Relationship Drug Temperature Cancer medicine.disease Flow Cytometry Recombinant Proteins Killer Cells Natural Mice Inbred C57BL Kinetics medicine.anatomical_structure Cytokine Liver Immunology Mutation Leukocytes Mononuclear Mutagenesis Site-Directed Molecular Medicine Interleukin-2 Cell Division Neoplasm Transplantation Biotechnology medicine.drug Protein Binding |
| Zdroj: | Nature biotechnology. 18(11) |
| ISSN: | 1087-0156 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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