IL-2 mutein-engrafted antibody MHS552 selectively expands functional regulatory T cells in nonclinical models and healthy participants

Abstract

Low-dose interleukin-2 (IL-2) shows potential for treating autoimmune disorders by expanding regulatory T cells (Treg), but therapeutic utility is limited by short half-life and off-target effects. Here, we describe the molecular design, nonclinical development, and first-in-human study of MHS552, an IL-2 mutein-engrafted antibody designed to selectively expand Treg via high-affinity IL-2 receptors. In vitro, MHS552 selectively induces IL-2 signaling in Treg from healthy donors and autoimmune patients. In cynomolgus monkeys, MHS552 produces dose-dependent Treg expansion, with modest increases in conventional T cells (Tconv) at higher doses. In a randomized, double-blind, placebo-controlled, single-ascending-dose trial in 60 healthy participants (EudraCT 2018-004233-33), evaluating safety and tolerability as the primary objective and pharmacokinetics as the secondary objective, intravenous and subcutaneous administration of MHS552 is well tolerated at lower doses and shows a predictable pharmacokinetic profile. However, a serious adverse event (SAE) is reported at the highest subcutaneous dose. Both administration routes result in dose-dependent Treg expansion, with up to 6-fold increase in total Treg and 60-fold increase in CD25hi subset, without significant conventional T cell activation. Exploratory analyses confirm selective Treg activation, with expanded Treg retaining their suppressive function ex vivo. These findings support IL-2-based therapeutics for autoimmune disorders, while the SAE highlights the need for careful safety evaluation. Although low-dose IL-2 therapy has shown promise in treating autoimmune and inflammatory conditions by supporting the expansion and immunosuppressive activity of regulatory T cells (Treg), robust clinical responses have been lacking. Here, the authors describe the design of the Treg-selective IL-2 agonist MHS552, its preclinical characterization in non-human primates, and a first-in-human dose escalation study in healthy participants reporting efficacy, selectivity and safety of the IL-2 mutein.