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Immunity. 2015 May 19;42(5):826-38. doi: 10.1016/j.immuni.2015.04.018.

Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps.

Author information

1
Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892-1674, USA.
2
Howard Hughes Medical Institute and Department of Molecular and Cellular Physiology and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
Experimental Transplantation and Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
4
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892-1374, USA.
5
Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
6
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA.
7
Howard Hughes Medical Institute and Department of Molecular and Cellular Physiology and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: kcgarcia@stanford.edu.
8
Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892-1674, USA. Electronic address: wjl@helix.nih.gov.

Abstract

Interleukin-2 (IL-2) regulates lymphocyte function by signaling through heterodimerization of the IL-2Rβ and γc receptor subunits. IL-2 is of considerable therapeutic interest, but harnessing its actions in a controllable manner remains a challenge. Previously, we have engineered an IL-2 "superkine" with enhanced affinity for IL-2Rβ. Here, we describe next-generation IL-2 variants that function as "receptor signaling clamps." They retained high affinity for IL-2Rβ, inhibiting binding of endogenous IL-2, but their interaction with γc was weakened, attenuating IL-2Rβ-γc heterodimerization. These IL-2 analogs acted as partial agonists and differentially affected lymphocytes poised at distinct activation thresholds. Moreover, one variant, H9-RETR, antagonized IL-2 and IL-15 better than blocking antibodies against IL-2Rα or IL-2Rβ. Furthermore, this mutein prolonged survival in a model of graft-versus-host disease and blocked spontaneous proliferation of smoldering adult T cell leukemia (ATL) T cells. This receptor-clamping approach might be a general mechanism-based strategy for engineering cytokine partial agonists for therapeutic immunomodulation.

PMID:
25992859
PMCID:
PMC4560365
DOI:
10.1016/j.immuni.2015.04.018
[Indexed for MEDLINE]
Free PMC Article

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