A cyclic peptide-grafted Fc with hepatocyte growth factor functionality ameliorates hepatic fibrosis in a non-alcoholic steatohepatitis mouse model

The regenerative functions associated with cytokines and growth factors have immense therapeutic potential; however, their poor pharmacokinetics, resulting from structural features, hinder their effectiveness. In this study, we aimed to enhance the pharmacokinetics of growth factors by designing receptor-binding macrocyclic peptides through in vitro mRNA display and grafting them into loops of immunoglobulin's crystallizable region (Fc). As a model, we developed peptide-grafted Fc proteins with hepatocyte growth factor (HGF) functionality that exhibited a prolonged circulation half-life and could be administered subcutaneously. The Fc-based HGF mimetic alleviated liver fibrosis in a mouse model fed a choline-deficient high-fat diet, which induces hepatic features of non-alcoholic steatohepatitis, including fibrosis, showcasing its potential as a therapeutic intervention. This study provides a basis for developing growth factor and cytokine mimetics with improved pharmacokinetics, expanding their therapeutic applications.

细胞因子与生长因子所介导的再生功能具有极高的治疗潜力；然而，其因结构特性导致的药代动力学（pharmacokinetics）缺陷，会大幅降低其治疗效能。本研究通过体外mRNA展示（in vitro mRNA display）技术设计受体结合型大环肽（macrocyclic peptide），并将其接枝至免疫球蛋白可结晶片段（Fc）的环区中，以此改善生长因子的药代动力学特性。本研究以具备肝细胞生长因子（HGF）功能的肽接枝Fc蛋白为模型，该蛋白展现出更长的循环半衰期，且可实现皮下注射给药。该基于Fc的HGF模拟物，在胆碱缺乏高脂饮食诱导的、带有肝纤维化等非酒精性脂肪性肝炎（non-alcoholic steatohepatitis）肝脏特征的小鼠模型中，可有效缓解肝纤维化，证实了其作为治疗干预手段的潜力。本研究为开发具备更优药代动力学特性的生长因子与细胞因子模拟物提供了重要基础，进一步拓展了其治疗应用范围。