ArticleNature communications2026
Engineering trispecific IL-2 receptor agonistic antibodies through geometry optimization for enhanced Treg targeting.
Article in Nature communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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.
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