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PubMed · 14983090

Interleukin-2 mutants with enhanced alpha-receptor subunit binding affinity.

Balaji M Rao·Andrew T Girvin·Thomas Ciardelli·Douglas A Lauffenburger·K Dane Wittrup
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Abstract

Stimulation of T-cells by IL-2 has been exploited for treatment of metastatic renal carcinoma and melanoma. However, a narrow therapeutic window delimited by negligible stimulation of T-cells at low picomolar concentrations and undesirable stimulation of NK cells at nanomolar concentrations hampers IL-2-based therapies. We hypothesized that increasing the affinity of IL-2 for IL-2Ralpha may create a class of IL-2 mutants with increased biological potency as compared with wild-type IL-2. Towards this end, we have screened libraries of mutated IL-2 displayed on the surface of yeast and isolated mutants with a 15-30-fold improved affinity for the IL-2Ralpha subunit. These mutants do not exhibit appreciably altered bioactivity at 0.5-5 pM in steady-state bioassays, concentrations well below the IL-2Ralpha equilibrium binding constant for both the mutant and wild-type IL-2. A mutant was serendipitously identified that exhibited somewhat improved potency, perhaps via altered endocytic trafficking mechanisms described previously.

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Cell DivisionCloning, MolecularInterleukin-2Interleukin-2 Receptor alpha SubunitMutationProtein BindingReceptors, InterleukinSaccharomyces cerevisiaeJournal ArticleResearch Support, Non-U.S. Gov't

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Balaji M Rao, Andrew T Girvin, Thomas Ciardelli, Douglas A Lauffenburger, K Dane Wittrup. 2003. Interleukin-2 mutants with enhanced alpha-receptor subunit binding affinity.. https://doi.org/10.1093/protein%2Fgzg111

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