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, IL-11–6M, in a mouse model of unilateral ureteral obstruction (UUO). We generated additional IL-11–6M variants via an optimized Escherichia coli expression system, with one variant (D46C) exhibiting comparable efficacy. Further modified through cysteine-specific PEGylation, analogue 13 demonstrated similar potency to IL-11–6M with an IC50 value of 61.5 ± 26.2 nM and maintained strong binding affinity to IL-11Rα (KD = 3.0 nM). Notably, analogue 13 exhibited a prolonged half-life and showed significant therapeutic effects in the UUO-induced renal fibrosis model. These findings suggest analogue 13 should be a promising candidate for the treatment of renal fibrosis.

肾纤维化作为慢性肾脏病（chronic kidney disease, CKD）进展的核心病理进程，仍是肾脏病学领域的重大挑战，目前尚无美国食品药品监督管理局（FDA）批准的专门靶向该病症的治疗药物。白细胞介素-11（Interleukin-11, IL-11）已被证实为肾纤维化的潜在治疗靶点。本研究在单侧输尿管梗阻（unilateral ureteral obstruction, UUO）小鼠模型中，验证了重组人IL-11类似物IL-11–6M的抗纤维化作用。我们通过优化的大肠杆菌（Escherichia coli）表达体系，制备了多款IL-11–6M的衍生变体，其中变体D46C展现出相当的药效活性。经半胱氨酸特异性聚乙二醇化（cysteine-specific PEGylation）进一步修饰后，类似物13的药效活性与IL-11–6M相当，其半最大效应浓度（IC50）为61.5 ± 26.2 nM，且对IL-11Rα仍保持较强的结合亲和力，解离常数（KD）为3.0 nM。值得注意的是，类似物13的半衰期显著延长，并在UUO诱导的肾纤维化模型中展现出显著的治疗效果。上述研究结果表明，类似物13有望成为治疗肾纤维化的极具潜力的候选药物。