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A Novel IL-2 Mutein Selectively Expands Regulatory T Cells and Prolongs Skin Graft Survival

O. Efe1, T. J. Borges1, R. B. Gassen1, L. Morena1, A. Al Jurdi1, I. T. Lape1, G. J. Bobcock2, J. C. Madsen1, L. V. Riella1

1Center for Transplantation Sciences, Massachusetts General Hospital, Charlestown, MA, 2Visterra, Inc., Waltham, MA

Meeting: 2022 American Transplant Congress

Abstract number: 584

Keywords: Graft survival, Immunosuppression, Interleukin-2 receptor, Tolerance

Topic: Basic Science » Basic Science » 10 - Treg/Other Regulatory Cell/Tolerance

Session Information

Session Name: Tregs and Tolerance

Session Type: Rapid Fire Oral Abstract

Date: Tuesday, June 7, 2022

Session Time: 5:30pm-7:00pm

 Presentation Time: 6:10pm-6:20pm

Location: Hynes Room 304 / 306

*Purpose: Promoting immune regulation through expansion of regulatory T cell (Treg) may allow immunosuppression minimization and improve long-term graft outcomes. Low-dose IL-2 is known to expand Tregs but its short half-life and off-target expansion of NK and CD8 T cells limits its clinical applicability. Here, we show the effects of a novel mutein IL-2 (mIL-2) that has increased Treg selectivity and improved pharmacokinetics through conjugation with an antibody Fc portion.

*Methods: First, we treated mouse splenocytes in vitro with mIL-2, WT Fc-IL-2 or negative control and measured the levels of phosphorylated STAT5 (pSTAT5), a downstream effector of IL-2 receptor in various immune cells. Next, we studied in vivo effects of single-dose and sustained-dose (twice a week for 3 weeks) mIL-2 treatment in B6 mice. Splenocytes from these mice were evaluated for Treg functional markers and cytokine production by flow cytometry. Lastly, we tested mIL-2 in two minor mismatch skin transplant models: male to female B6 and OVA to B6; as well as rechallenged with allo or third-party grafts. Recipients were subcutaneously treated twice a week with 0.5 mg/kg of mIL-2 or control IgG.

*Results: mIL-2 increased levels of pSTAT5 selectively in Tregs in a wide dose range but not in NK or CD8 T cells. In vivo, single dose mIL-2 increased circulating Tregs up to 40% of CD4+ T cells by day 4 with an effect lasting for 7 days. Sustained mIL-2 treatment led to stable expansion of circulating Tregs at 40-50 % without expanding effector cells and a 5.3-fold rise in splenic Tregs (Fig.1A). Regarding functional suppressive markers, mIL-2 increased % of CTLA-4+, TGF-b+, and IL-10+ splenic Tregs at day 4 after single injection (Fig.1B). In male to female skin transplant model, mIL-2 led to a sustained Treg expansion without affecting NK cells (Fig.1C) or CD8 T cells (not shown). It also prolonged median graft survival (MGS) to >185 days vs 34.5 days (p=0.0004) in the control group (Fig.1D). Treatments were stopped, and recipients were challenged with a similar allo-skin or third-party skin (male B6 or OVA B6, respectively). Second male skin grafts survived long-term while third-party grafts rejected early, indicating antigen-specific tolerance (MGS >65 vs 17 days, respectively, p<0.001). Lastly, mIL-2 also prolonged graft survival in OVA to B6 recipient mice (MGS 13 vs >30 days, p=0.01).

*Conclusions: mIL-2 selectively expands Tregs, increases CTLA-4+ Tregs, and prolongs skin graft survival in mice.

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To cite this abstract in AMA style:

Efe O, Borges TJ, Gassen RB, Morena L, Jurdi AAl, Lape IT, Bobcock GJ, Madsen JC, Riella LV. A Novel IL-2 Mutein Selectively Expands Regulatory T Cells and Prolongs Skin Graft Survival [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/a-novel-il-2-mutein-selectively-expands-regulatory-t-cells-and-prolongs-skin-graft-survival/. Accessed May 26, 2025.

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