Arthritis & rheumatology 73, 5, 769-778 (2021)
Suppression of Rheumatoid Arthritis by Enhanced Lymph Node Trafficking of Engineered Interleukin-10 in Murine Models


Eiji Yuba, Erica Budina, Kiyomitsu Katsumata, Ako Ishihara, Aslan Mansurov, Aaron T Alpar, Elyse A Watkins, Peyman Hosseinchi, Joseph W Reda, Abigail L Lauterbach, Mindy Nguyen, Ani Solanki, Takahiro Kageyama, Melody A Swartz, Jun Ishihara#, Jeffrey A Hubbell#




Objective Rheumatoid arthritis (RA) is a major autoimmune disease that causes synovitis and joint damage. Although clinical trials have been performed using interleukin-10 (IL-10), an antiinflammatory cytokine, as a potential treatment of RA, the therapeutic effects of IL-10 have been limited, potentially due to insufficient residence in lymphoid organs, where antigen recognition primarily occurs. This study was undertaken to engineer an IL-10–serum albumin (SA) fusion protein and evaluate its effects in 2 murine models of RA. Methods SA-fused IL-10 (SA–IL-10) was recombinantly expressed. Mice with collagen antibody–induced arthritis (n = 4–7 per group) or collagen-induced arthritis (n = 9–15 per group) were injected intravenously with wild-type IL-10 or SA–IL-10, and the retention of SA–IL-10 in the lymph nodes (LNs), immune cell composition in the paws, and therapeutic effect of SA–IL-10 on mice with arthritis were assessed. Results SA fusion to IL-10 led to enhanced accumulation in the mouse LNs compared with unmodified IL-10. Intravenous SA–IL-10 treatment restored immune cell composition in the paws to a normal status, elevated the frequency of suppressive alternatively activated macrophages, reduced IL-17A levels in the paw-draining LN, and protected joint morphology. Intravenous SA–IL-10 treatment showed similar efficacy as treatment with an anti–tumor necrosis factor antibody. SA–IL-10 was equally effective when administered intravenously, locally, or subcutaneously, which is a benefit for clinical translation of this molecule. Conclusion SA fusion to IL-10 is a simple but effective engineering strategy for RA therapy and has potential for clinical translation.