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Protein Engineering vol. 16 no. 12 pp. 1081-1087, 2003
© 2003 Oxford University Press

Interleukin-2 mutants with enhanced {alpha}-receptor subunit binding affinity

Balaji M. Rao1, Andrew T. Girvin1, Thomas Ciardelli2, Douglas A. Lauffenburger1 and K.Dane Wittrup1,3

1Department of Chemical Engineering and Biological Engineering Division, Massachusetts Institute of Technology, MIT 66-552, Cambridge, MA 02139 and 2Dartmouth Medical School, Hanover, NH 03755, USA

3 To whom correspondence should be addressed. e-mail: wittrup{at}mit.edu

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-2R{alpha} 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-2R{alpha} subunit. These mutants do not exhibit appreciably altered bioactivity at 0.5–5 pM in steady-state bioassays, concentrations well below the IL-2R{alpha} 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.

Received June 13, 2003; revised July 30, 2003; accepted September 26, 2003


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