Interleukin 2 (IL-2) variants engineered for increased IL-2 receptor alpha-subunit affinity exhibit increased potency arising from a cell surface ligand reservoir effect

Molecular Pharmacology
Balaji M RaoK Dane Wittrup

Abstract

Proliferation of activated T cells and CD56 bright natural killer (Cytokine Growth Factor Rev 13:169-183, 1995) cells caused by interleukin-2 (IL-2) has been exploited in IL-2-based therapies for the treatment of metastatic renal cell carcinoma and melanoma (J Clin Oncol 13:688-696, 1995; J Clin Oncol 17: 2105-2116, 1999). In this study, we demonstrate the potentially improved therapeutic value of IL-2 variants engineered to gain 15- to 30-fold increased affinity for the IL-2 receptor alpha-subunit (IL-2Ralpha). A novel pulsed bioassay was used to more closely approximate the rapid systemic clearance pharmacokinetics of cytokines such as IL-2, compared with conventional static bioassays. In this assay, mutants with increased affinity for IL-2Ralpha exhibit significantly increased activity for T-cell proliferation, whereas static bioassays not only fail to reveal the increased activity resulting from enhanced IL-2Ralpha affinity (false negatives), but also suggest improved activity for another mutant without enhanced activity in the pulsed assay (false positive). Our studies on the mechanism leading to increased activity of IL-2 mutants with increased IL-2Ralpha affinity suggest that cell-surface IL-2Ralpha acts as a ligand rese...Continue Reading

Citations

Jul 30, 2016·Oncoimmunology·Tao JiangShengxiang Ren
Oct 16, 2018·Frontiers in Immunology·Claire GorbyIgnacio Moraga

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