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

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A Corrigendum to this article was published on 01 December 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 ∼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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Figure 1: Structural representation of IL-2 and hypothesis for receptor.
Figure 2: In vitro activity of BAY 50-4798.
Figure 3: Renal and hepatic function of treated chimpanzees.
Figure 4: FACS analysis of cells from BAY 50-4798- and Proleukin-treated chimpanzee blood.
Figure 5: Effects of BAY 50-4798 and Proleukin on hematological parameters of treated chimpanzees.
Figure 6: BAY 50-4798 and Proleukin treatment of B16 lung metastasis-bearing mice.

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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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Author notes

  1. Armen B. Shanafelt

    Present address: Roche Diagnostics Corporation, 9115 Hague Road, Indianapolis, IN, 46250

  2. Yue Lin

    Present address: FibroGen, Inc., 225 Gateway Blvd., South San Francisco, CA, 94080

  3. Robert Gundel

    Present address: Chiron Corporation, 4560 Horton Street, Emeryville, CA, 94608

Authors and Affiliations

  1. Pharmaceutical Division, Research, Biotechnology, Bayer Corporation, 800 Dwight Way, Berkeley, 94701, CA

    Armen B. Shanafelt, Yue Lin, Marie-Claude Shanafelt, Carla P. Forte, Nathalie Dubois-Stringfellow, Jacqueline A. Gibbons, Katherine A. Delaria, Richard Fleischer, Jeffrey M. Greve, Robert Gundel, Polly Mak, Lauri Neyer, Steve Roczniak, Daniel Serban, Linda Tsuchiyama, Monte Wetzel & Alya Zolotorev

  2. Bayer Corporation Pharmaceutical Division, Process Sciences, Biotechnology, 800 Dwight Way, Berkeley , 94701, CA

    Shu-lan Cheng, Kathleen Harris, Ruth Kelly, Beth Koh, Ying Li, John Thrift & Mel Wong

  3. Department of Cancer and Osteoporosis Research, Pharmaceutical Division, Bayer Corporation, 400 Morgan Lane, West Haven, 06556, CT

    Christopher Carter, Lori Lantz & Mary Jane Plym

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  1. Armen B. Shanafelt
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Correspondence to Armen B. Shanafelt.

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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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