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Published on: May 9, 2025
Engineering trispecific IL-2 receptor agonistic antibodies through geometry optimization for enhanced Treg targeting
Valentina Lykhopiy1,2, Emilie Pollenus3, Laurie Rangan3
1argenx, Zwijnaarde, Belgium. vlykhopiy@argenx.com.
Nature Communications
|July 10, 2026
Summary
Researchers developed novel trispecific antibodies to selectively activate regulatory T cells (Tregs) using interleukin-2 receptor (IL-2R) signaling. This approach offers a promising therapeutic strategy for autoimmune diseases and transplant rejection by enhancing immune tolerance.
Area of Science:
- Immunology
- Biotechnology
- Pharmacology
Background:
- Regulatory T cells (Tregs) are crucial for immune tolerance.
- Interleukin-2 (IL-2) signaling selectively activates Tregs.
- Targeting IL-2R is a potential therapy for autoimmune diseases and transplant rejection.
Purpose of the Study:
- To develop novel IL-2 receptor (IL-2R) agonists with enhanced Treg selectivity.
- To investigate the therapeutic potential of trispecific antibodies for immune modulation.
Main Methods:
- Design and engineering of trispecific antibodies targeting all three IL-2R subunits.
- Incorporation of a CD25-targeting VHH domain for increased specificity.
- Optimization of antibody geometry for maximal Treg selectivity.
Main Results:
- Developed trispecific IL-2R agonists that preferentially activate and expand Tregs.
- Demonstrated enhanced specificity and potency for CD25+ Tregs.
- Highlighted the critical role of antibody spatial configuration in receptor engagement.
Conclusions:
- Successful development of a versatile platform of trispecific IL-2R-targeting antibodies.
- This platform selectively activates the high-affinity trimeric IL-2R on Tregs.
- Offers a promising and differentiated strategy for treating autoimmune diseases and transplant rejection.
