Abstract
The preferential activation of regulatory T (Treg) cells by interleukin-2 (IL-2), which selectively binds to the trimeric IL-2 receptor (IL-2R) on Treg cells, makes this cytokine a promising therapeutic for the treatment of autoimmune diseases. However, IL-2 has a narrow therapeutic window and a short half-life. Here, we show that the pharmacokinetics and half-life of IL-2 can be substantially improved by orthogonally conjugating the cytokine to poly(ethylene glycol) (PEG) moieties via a copper-free click reaction through the incorporation of azide-bearing amino acids at defined sites. Subcutaneous injection of a PEGylated IL-2 that optimally induced sustained Treg-cell activation and expansion over a wide range of doses through highly selective binding to trimeric IL-2R led to enhanced therapeutic efficacy in mouse models of lupus, collagen-induced arthritis and graft-versus-host disease without compromising the immune defences of the host against viral infection. Site-specific PEGylation could be used more generally to engineer cytokines with improved therapeutic performance for the treatment of autoimmune diseases.
【초록키워드】 Treatment, Arthritis, viral infection, cytokine, immune, Regulatory, therapeutic, PEGylation, Autoimmune diseases, mouse model, disease, Treg, binding, IL-2, Amino acid, dose, therapeutic window, glycol, Subcutaneous, IL-2 receptor, Activation, therapeutic efficacy, injection, Treg cells, selective, Host, Cell, trimeric, bind, defined, sustained, activation and expansion, 【제목키워드】 Immunosuppression, Regulatory T cell, PEGylation, Activation, ENhance, sustained,