Activity-attenuated serum albumin-fused interleukin-33 suppresses experimental autoimmune encephalomyelitis

Interleukin-33 (IL-33) is an immunoregulatory cytokine that moderately suppresses experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). However, poor pharmacokinetics and toxicity hinder its clinical translation. To address these limitations, we develop an activity-attenuated IL-33 by recombinant fusion to serum albumin (SA). SA-IL-33 exhibits reduced toxicity and prolonged residence in the secondary lymphoid organs (SLOs), sites of T cell priming in autoimmunity, compared to wild-type (WT) IL-33. Prophylactic SA-IL-33 administration prevents EAE with superior efficacy to WT IL-33 and comparable efficacy to fingolimod (FTY720), a Food and Drug Administration (FDA)-approved MS drug. Therapeutic SA-IL-33 treatment also reduces disease severity in both chronic and relapsing-remitting EAE. SA-IL-33 modulates immunity in EAE by suppressing CD45⁺ cell infiltration (including myelin-reactive T helper 17 [T_H17] cells) in the spinal cord, while expanding type 2 immune cells (including type 2 innate lymphoid cells [ILC2s], ST2⁺ regulatory T cells [Tregs], T helper 2 [T_H2] cells, and M2-polarized macrophages) in the SLOs. These findings suggest that SA-IL-33 is a promising therapeutic for neuroinflammatory diseases.