mRNA encoding IL-2 mutant protein for the treatment of autoimmune diseases

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mRNA encoding IL-2 mutant protein for the treatment of autoimmune diseases

Moderna’s latest paper: mRNA encoding IL-2 mutant protein for the treatment of autoimmune diseases

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

First discovered in 1983, IL-2 was rapidly translated into a treatment regimen 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 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, and these two receptors 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 could improve disease outcomes.

Because low-dose IL-2 selectively expands Tregs, it has been clinically tested in chronic graft-versus-host disease (cGvHD) , systemic lupus erythematosus, and several other autoimmune diseases, and has been observed inspiring effect.

However, current low-dose IL-2 therapies have some 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 destabilizing mutations or by epitope masking.

On July 5, 2022, Eric Huang et al . from Moderna published in the journal Nature Communications : Selective activation and expansion of regulatory T cells using lipid encapsulated mRNA encoding a long-acting IL-2 mutein (using lipid encapsulated mRNA). mRNA encoding a long-acting IL-2 mutein selectively activates and expands regulatory T cells) .

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

Moderna's latest paper: mRNA encoding IL-2 mutant protein for the treatment of autoimmune diseases

mRNA is emerging as a promising technology for many diseases, multiple clinical trials are underway, and it has been demonstrated preclinically and clinically that mRNA can exert both preventive and therapeutic effects on diseases by expressing proteins.

The research team hopes to express the IL-2 mutant protein with longer half-life through mRNA and design it to be receptor-selective (IL2RA) , which can selectively expand Tregs in vivo when mRNA is encapsulated and delivered using liposomes.

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

In vitro cell experiments showed that HSA-IL2m-induced STAT5 phosphorylation was observed only in Treg , distinguishing it from the wild-type IL-2 fusion protein (HSA – IL2wt) that induces STAT5 phosphorylation in NK cells and conventional T cells Come.

The research team further conducted in vivo 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.

HSA-IL2m mRNA delivered by lipid encapsulation can selectively activate and expand Treg continuously, thereby reducing graft-versus-host disease (GvHD) mouse models and autoimmune encephalomyelitis (EAE) mouse models. Disease severity.

Moderna's latest paper: mRNA encoding IL-2 mutant protein for the treatment of autoimmune diseases