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A humanized IL-2 mutein expands Tregs and prolongs transplant survival in preclinical models
Orhan Efe, … , Thiago J. Borges, Leonardo V. Riella
Orhan Efe, … , Thiago J. Borges, Leonardo V. Riella
Published March 1, 2024
Citation Information: J Clin Invest. 2024;134(5):e173107. https://doi.org/10.1172/JCI173107.
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Research Article Immunology Article has an altmetric score of 37

A humanized IL-2 mutein expands Tregs and prolongs transplant survival in preclinical models

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Abstract

Long-term organ transplant survival remains suboptimal, and life-long immunosuppression predisposes transplant recipients to an increased risk of infection, malignancy, and kidney toxicity. Promoting the regulatory arm of the immune system by expanding Tregs may allow immunosuppression minimization and improve long-term graft outcomes. While low-dose IL-2 treatment can expand Tregs, it has a short half-life and off-target expansion of NK and effector T cells, limiting its clinical applicability. Here, we designed a humanized mutein IL-2 with high Treg selectivity and a prolonged half-life due to the fusion of an Fc domain, which we termed mIL-2. We showed selective and sustainable Treg expansion by mIL-2 in 2 murine models of skin transplantation. This expansion led to donor-specific tolerance through robust increases in polyclonal and antigen-specific Tregs, along with enhanced Treg-suppressive function. We also showed that Treg expansion by mIL-2 could overcome the failure of calcineurin inhibitors or costimulation blockade to prolong the survival of major-mismatched skin grafts. Validating its translational potential, mIL-2 induced a selective and sustainable in vivo Treg expansion in cynomolgus monkeys and showed selectivity for human Tregs in vitro and in a humanized mouse model. This work demonstrated that mIL-2 can enhance immune regulation and promote long-term allograft survival, potentially minimizing immunosuppression.

Authors

Orhan Efe, Rodrigo B. Gassen, Leela Morena, Yoshikazu Ganchiku, Ayman Al Jurdi, Isadora T. Lape, Pedro Ventura-Aguiar, Christian LeGuern, Joren C. Madsen, Zachary Shriver, Gregory J. Babcock, Thiago J. Borges, Leonardo V. Riella

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Figure 2

The Treg specificity and pharmacokinetics of mIL-2.

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The Treg specificity and pharmacokinetics of mIL-2.
(A) Bioavailability ...
(A) Bioavailability of intravenous mIL-2 (0.25 mg/kg) compared with equimolar human IgG1 (1.5 mg/kg) in hFcRn-transgenic Tg32 mice, indicating its prolonged half-life (n = 3/group, data are from a single experiment). (B) Illustration showing the selective binding of mIL-2 to Tregs but not to effector immune cells due to constitutive IL-2Rα (CD25) expression on Tregs. Flow cytometric analyses of p-STAT5 (pY694) levels in splenic (C) Tregs, (D) CD8+ T cells, (E) NK cells, and (F) eosinophils after a 30-minute in vitro stimulation with control IgG, mIL-2, or Fc–IL-2 at increasing concentrations (n = 5/group, data were pooled from 3 independent experiments). Graphs show the mean ± SD and 1-way ANOVA and Tukey’s multiple-comparison test were used for group comparisons (C–F).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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