MRNA Encoding IL-2 Mutein Is Used to Treat Autoimmune Diseases

Interleukin 2 (IL-2) is essential for the growth, survival and function of T cells and maintains immune homeostasis.

IL-2, first discovered in 1983, was rapidly translated into a treatment option for renal cell carcinoma and melanoma the following year, and was approved as the first immunotherapy in 1992.

Subsequent studies confirmed that IL-2 plays an important role in the survival and proliferation of regulatory T cells (Treg).

IL-2 stimulates Treg only limitedly at low concentrations, while at high concentrations it stimulates all T cells, as well as natural killer (NK) cells. This is because IL-2 has two receptors with different affinities that are expressed differently on different immune cells.

Early studies have shown that regulatory T cells (Treg) are defective in number and/or function in various human autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, etc. Interventions that increase functional Tregs in these patients can improve disease outcomes.

Because low-dose IL-2 selectively expands Tregs, clinical trials have been conducted in chronic graft-versus-host disease (cGvHD), systemic lupus erythematosus, and several other autoimmune diseases, and encouraging effects have been observed.

However, current low-dose IL-2 therapy has several limitations, including pro-inflammatory effects on various cell populations, and poor pharmacokinetics.

To address these issues, there are currently several strategies based on protein engineering to increase the half-life of IL-2 and its specificity for Treg.

Typically, these approaches attenuate the interaction of IL-2 with IL2RB and increase the interaction with IL2RA by disrupting mutation or epitope masking.

Recently, Eric Huang et al. published an article in Nature Communications: Selective activation and expansion of regulatory T cells using lipid encapsulated mRNA encoding a long-acting IL-2 mutein.

This study demonstrates that lipid-delivered mRNA encoding HSA-IL2m has the potential to treat autoimmune diseases.

As a promising technology for the treatment of various diseases, mRNA is undergoing a number of clinical trials. It has been demonstrated both preclinically and clinically that mRNA can play a dual role in disease prevention and treatment by expressing proteins.

The team hopes to selectively expand Tregs in vivo by expressing IL-2 mutant proteins with a long half-life in mRNA and designing them as receptor-selective (IL2RA), encapsulating and delivering mRNA through liposomes.

In this study, the research team introduced three mutants of human IL-2 and serum albumin fused to form a long-acting mutant IL-2 fusion protein HSA-IL2m.

In vitro cell experiments showed that HSA-IL2m-induced STAT5 phosphorylation occurred only in Treg, unlike wild-type IL-2 fusion protein (HSA-IL2wt) that induced STAT5 phosphorylation in NK cells and conventional T cells.

The research team further conducted experiments in mice, rats and non-human primates, and the results showed that the mRNA form of HSA-IL2m can selectively expand Tregs without activating NK cells and conventional T cells.

Lipid-encapsulated delivered HSA-IL2m mRNA selectively and continuously activates and dilates Treg, thereby reducing disease severity in a mouse model of graft-versus-host disease (GvHD) and a mouse model of autoimmune encephalomyelitis (EAE).

These results demonstrate the potential of mRNA-encoded HSA-IL2m immunotherapy for the treatment of autoimmune diseases.

Collected by Creative BioMart, a recombinant protein provider.