Development of a Long-Acting Interleukin-11 Antagonist for the Treatment of Renal Fibrosis

Renal fibrosis, a key progression of chronic kidney disease (CKD), remains a major challenge in nephrology, with no FDA-approved drugs specifically targeting this condition. Interleukin-11 (IL-11) has emerged as a potential therapeutic target for renal fibrosis. In this study, we identified the antifibrotic effects of a recombinant human IL-11 analogue, <b>IL-11-6M</b>, in a mouse model of unilateral ureteral obstruction (UUO). We generated additional <b>IL-11-6M</b> variants via an optimized <i>Escherichia coli</i> expression system, with one variant (D46C) exhibiting comparable efficacy. Further modified through cysteine-specific PEGylation, analogue <b>13</b> demonstrated similar potency to <b>IL-11-6M</b> with an IC₅₀ value of 61.5 ± 26.2 nM and maintained strong binding affinity to IL-11Rα (<i>K</i>_D = 3.0 nM). Notably, analogue <b>13</b> exhibited a prolonged half-life and showed significant therapeutic effects in the UUO-induced renal fibrosis model. These findings suggest analogue <b>13</b> should be a promising candidate for the treatment of renal fibrosis.