Engineered receptor-biased IL-2–drug immunoconjugates selectively expand Tregs and suppress effector cells for autoimmune therapy

Interleukin-2 (IL-2) supports both Treg maintenance and effector cells responses, necessitating careful dose optimization for selective immune regulation. Here, we report an immunoconjugate strategy that integrates Treg-selective cytokine signalling with localized pharmacological suppression by coupling a site-specifically PEGylated IL-2 variant (Y31-20K) to immunosuppressive small molecules.

Through systematic screening, we identify Y31-20K-KU as the lead construct, which restores immune homeostasis in patient-derived lymphocytes and ameliorates pathology in mouse models of chronic colitis and collagen-induced arthritis. Mechanistically, Y31-20K-KU selectively expands Tregs while concurrently suppressing effector cells, and exhibited favourable safety with minimal immunogenicity, thereby overcoming limitations of cytokine- and small-molecule-based monotherapies.