当前位置： SCI文献检索 > MOLECULAR PHARMACOLOGY期刊下所有文献 > 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.

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.

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 reservoir for the IL-2 mutants. This leads to increased cell-surface persistence of the IL-2 mutants with increased IL-2Ralpha 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-2Ralpha-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.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Rao BM,Driver I,Lauffenburger DA,Wittrup KD

doi

10.1124/mol.66.4.

keywords:

subject

Has Abstract

pub_date

2004-10-01 00:00:00

pages

864-9

issue

4

eissn

0026-895X

issn

1521-0111

pii

66/4/864

journal_volume

66

pub_type

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