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Molecular Pharmacology

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Research ArticleArticle

Interleukin 2 (IL-2) Variants Engineered for Increased IL-2 Receptor α-Subunit Affinity Exhibit Increased Potency Arising from a Cell Surface Ligand Reservoir Effect

Balaji M. Rao, Ian Driver, Douglas A. Lauffenburger and K. Dane Wittrup
Molecular Pharmacology October 2004, 66 (4) 864-869; DOI: https://doi.org/10.1124/mol.66.4.864
Balaji M. Rao
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Ian Driver
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Douglas A. Lauffenburger
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K. Dane Wittrup
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Abstract

Proliferation of activated T cells and CD56 bright natural killer (

Cytokine Growth Factor Rev13:169-183, 1995
OpenUrl

) 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 Oncol13:688-696, 1995
OpenUrlAbstract/FREE Full Text

;

J Clin Oncol17: 2105-2116, 1999
OpenUrlAbstract/FREE Full Text

). 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 α-subunit (IL-2Rα). 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-2Rα exhibit significantly increased activity for T-cell proliferation, whereas static bioassays not only fail to reveal the increased activity resulting from enhanced IL-2Rα 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-2Rα affinity suggest that cell-surface IL-2Rα acts as a ligand reservoir for the IL-2 mutants. This leads to increased cell-surface persistence of the IL-2 mutants with increased IL-2Rα affinity in cell-surface ligand reservoirs and consequently increased integrated growth signal. Furthermore, a mathematical model predicts increased persistence of cell surface-bound IL-2 in vivo for enhanced IL-2Rα-binding IL-2 mutants, suggesting potentially improved therapeutic value of allowing cellular capture of ligands in persistent cell-surface reservoirs. Finally, our findings emphasize the critical choice of appropriate bioassays to evaluate engineered proteins and other drugs.

  • Received February 26, 2004.
  • Accepted July 14, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 66 (4)
Molecular Pharmacology
Vol. 66, Issue 4
1 Oct 2004
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Research ArticleArticle

Interleukin 2 (IL-2) Variants Engineered for Increased IL-2 Receptor α-Subunit Affinity Exhibit Increased Potency Arising from a Cell Surface Ligand Reservoir Effect

Balaji M. Rao, Ian Driver, Douglas A. Lauffenburger and K. Dane Wittrup
Molecular Pharmacology October 1, 2004, 66 (4) 864-869; DOI: https://doi.org/10.1124/mol.66.4.864

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Research ArticleArticle

Interleukin 2 (IL-2) Variants Engineered for Increased IL-2 Receptor α-Subunit Affinity Exhibit Increased Potency Arising from a Cell Surface Ligand Reservoir Effect

Balaji M. Rao, Ian Driver, Douglas A. Lauffenburger and K. Dane Wittrup
Molecular Pharmacology October 1, 2004, 66 (4) 864-869; DOI: https://doi.org/10.1124/mol.66.4.864
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