Interleukin-2 Activity Can Be Fine Tuned with Engineered Receptor Signaling Clamps

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2015 May 21

PMID 25992859

Citations 89

Authors

Suman Mitra

Aaron M Ring

Shoba Amarnath

Jamie B Spangler

Peng Li

Wei Ju

Suzanne Fischer

Jangsuk Oh

Rosanne Spolski

Kipp Weiskopf

Holbrook Kohrt

Jason E Foley

Sumati Rajagopalan

Eric O Long

Daniel H Fowler

Thomas A Waldmann

K Christopher Garcia

Warren J Leonard

Affiliations

Soon will be listed here.

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.

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