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<p>Regulatory T cells (Tregs) are central to maintaining immune tolerance, and their selective activation via interleukin-2 (IL-2) signaling presents a promising therapeutic strategy for autoimmune diseases and transplant rejection. Here, we develop IL-2 receptor (IL-2R) agonists, employing trispecific antibodies that simultaneously engage all three IL-2R subunits. This design preferentially activates and expands Tregs over conventional T cells and natural killer cells that express the dimeric IL-2R (CD122 and CD132). Incorporation of a second CD25-targeting VHH domain confers further enhanced specificity and potency for CD25⁺ Tregs. Extensive engineering of antibody geometry was then critical to maximize Treg selectivity, highlighting the importance of spatial configuration in receptor engagement. This study reports the successful development of trispecific IL-2R-targeting antibodies and significantly expands the potential of antibody-based immunomodulation. By selectively activating the high-affinity trimeric IL-2R on Tregs, this versatile platform offers a differentiated and promising strategy for the treatment of autoimmune diseases and transplant rejection.</p>

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Engineering trispecific IL-2 receptor agonistic antibodies through geometry optimization for enhanced Treg targeting

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月10日

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  • Valentina Lykhopiy,
  • Emilie Pollenus,
  • Laurie Rangan,
  • Michelle Stakenborg,
  • Tugsan Tezil,
  • Michiel Varheust,
  • Giel Tanghe,
  • Nina Lambrechts,
  • Vanshika Malviya,
  • Eva De Langhe,
  • Gianluca Matteoli,
  • Christophe Blanchetot,
  • Luc Van Rompaey,
  • Susan M. Schlenner

摘要

Regulatory T cells (Tregs) are central to maintaining immune tolerance, and their selective activation via interleukin-2 (IL-2) signaling presents a promising therapeutic strategy for autoimmune diseases and transplant rejection. Here, we develop IL-2 receptor (IL-2R) agonists, employing trispecific antibodies that simultaneously engage all three IL-2R subunits. This design preferentially activates and expands Tregs over conventional T cells and natural killer cells that express the dimeric IL-2R (CD122 and CD132). Incorporation of a second CD25-targeting VHH domain confers further enhanced specificity and potency for CD25⁺ Tregs. Extensive engineering of antibody geometry was then critical to maximize Treg selectivity, highlighting the importance of spatial configuration in receptor engagement. This study reports the successful development of trispecific IL-2R-targeting antibodies and significantly expands the potential of antibody-based immunomodulation. By selectively activating the high-affinity trimeric IL-2R on Tregs, this versatile platform offers a differentiated and promising strategy for the treatment of autoimmune diseases and transplant rejection.