Harnessing the Power of KKC80: A Selective and Long-Lasting IL-2 Variant for Autoimmune and Inflammatory Disorders

Regulatory T cells (Tregs) play a crucial role in managing autoimmune and inflammatory diseases, and their reduction or dysfunction is often associated with such conditions. Low-dose IL-2 therapy has shown promise in expanding Tregs and providing clinical benefits in diseases like systemic lupus erythematosus (SLE) and chronic graft-versus-host disease (GvHD). However, the therapy's short half-life and lack of Treg selectivity can lead to adverse events.

A new PEGylated IL-2 variant, KKC80, has been developed to address these challenges. It demonstrates high Treg selectivity, a prolonged half-life, and an improved therapeutic profile. The development of KKC80 was guided by the co-crystal structure of IL-2 and its receptor, with specific amino acid substitutions to allow for site-specific PEGylation using click chemistry.

The novel variant's binding properties were evaluated using surface plasmon resonance (SPR), revealing a moderate decrease in binding affinity to CD25 and a significant decrease in binding affinity to IL-2Rβγ. In vitro studies showed that KKC80 selectively activated Tregs, unlike wild-type IL-2, which activated both Tregs and NK cells. KKC80's Treg selectivity was comparable to an IL-2 mutein, Fc.IL-2 V91K, but unlike Fc.IL-2 V91K, KKC80 maintained its activity even in the presence of recombinant soluble CD25.

In vivo studies in cynomolgus monkeys showed that KKC80 dose-dependently increased peripheral blood Tregs, with a sustained upregulation of functional Treg markers and a calculated half-life of 83.5 to 150 hours. KKC80 was also found to ameliorate GvHD symptoms and suppress inflammation markers in a mouse xenogeneic GvHD model, indicating its Treg-mediated anti-inflammatory effects.

In conclusion, KKC80 offers a superior therapeutic index and efficacy profile compared to current IL-2 therapies, with its high Treg selectivity and anti-inflammatory effects. These properties suggest that KKC80 could be a promising treatment for patients with autoimmune and inflammatory diseases.