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

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

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 6

Assessment of antigen-specific tolerance after mIL-2 treatment and rechallenge with a second graft in 2 minor-mismatch skin transplant models.

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Assessment of antigen-specific tolerance after mIL-2 treatment and recha...
(A) Illustration of a female B6.mOVA to female WT B6 skin transplant model. (B) Kaplan-Meier graph showing the OVA graft survival in mIL-2 versus control groups and the days of mIL-2 treatment discontinuation (red dotted line) and the second skin transplantation (blue dotted line), respectively. (C) Illustration of the antigen-specific tolerance experiment, in which original OVA graft recipient mice were challenged with 2 additional grafts, including a similar graft and a third-party graft. (D) Kaplan-Meier graph showing the long-term survival of a second OVA graft and early rejection of a third-party (male) graft in the original OVA graft female recipients. Isograft, syngeneic graft. (E) Illustration of the experiment and (F) Kaplan-Meier graph showing the original graft survival, treatment discontinuation, and the timing of the second skin transplant in male to female B6 skin transplantation. (G) Illustration of the tolerance experiment in the original male graft recipients and (H) Kaplan-Meier graph showing the long-term survival of the second similar grafts (male graft) and early rejection of the third-party grafts (OVA graft). The long-rank test was used for graft survival comparisons (B, D, F, and H) (n = 3–12 animals/group, data were pooled from 5 independent experiments).