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 ∼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.
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Acknowledgements
We wish to acknowledge the analytical and technical assistance of the process development and fermentation groups of Bayer Biotechnology, the technical contributions of C. Meugge, U. Minocha, and L.M. Yang (research, biotechnology), H. Apeler, J. Peters, and K-H. Schneider (Bayer AG), C. Pan for molecular modeling of BAY 50-4798, T. Reynolds, M. Eckart, and J. Murphy for review and comments, and the guidance and support of T. Terrell and R. Zimmerman.
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Shanafelt, A., Lin, Y., Shanafelt, MC. et al. A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo. Nat Biotechnol 18, 1197–1202 (2000). https://doi.org/10.1038/81199
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DOI: https://doi.org/10.1038/81199
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