Engineering trispecific IL-2 receptor agonistic antibodies through geometry optimization for enhanced Treg targeting.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 42431912.
- Also identified by DOI 10.1038/s41467-026-75024-6.
- No licence information is recorded for this record.
- Because redistribution is not established, this page shows the abstract only. Follow the links below for the full text.
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.