α-1-微球蛋白(A1M)是一种循环糖蛋白,具有抗氧化剂,血红素结合和线粒体保护特性。研究药物RMC-035,一种修饰的治疗性A1M蛋白,在广泛的体外和体内实验中评估了生物分布和药理活性,支持其临床发展。在肾脏缺血和再灌注损伤(IRI)的各种模型中评估了功效和治疗方法。实时肾小球滤过率,功能性肾脏生物标志物,评估肾小管损伤生物标志物(NGAL和KIM-1)和组织病理学.荧光标记的RMC-035用于评估生物分布。RMC-035在大鼠IRI模型中表现出一致且可重复的肾脏保护作用,同样在对肾功能损害施加的IRI模型中,在小鼠IRI模型中,它降低了死亡率。在缺血前后联合给药的情况下,其药理活性最为明显,和较弱的前或后缺血单独给药。RMC-035通过肾小球滤过和近端肾小管细胞的选择性管腔摄取迅速分布到肾脏。RMC-035抑制了IRI诱导的肾血红素加氧酶-1的表达,与其抗氧化特性一致。RMC-035还抑制了IRI相关的炎症,并改善了管状自发荧光显示的线粒体功能。一起来看,RMC-035的疗效与其靶向机制和生物分布情况一致,并支持其作为新型肾脏保护性治疗的进一步临床评估.
α-1-Microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme-binding, and mitochondrial protection properties. The investigational drug RMC-035, a modified therapeutic A1M protein, was assessed for biodistribution and pharmacological activity in a broad set of in vitro and in vivo experiments, supporting its clinical development. Efficacy and treatment posology were assessed in various models of kidney ischemia and reperfusion injury (
IRI). Real-time glomerular filtration rate (GFR), functional renal biomarkers, tubular injury biomarkers (NGAL and KIM-1), and histopathology were evaluated. Fluorescently labeled RMC-035 was used to assess biodistribution. RMC-035 demonstrated consistent and reproducible kidney protection in rat
IRI models as well as in a model of
IRI imposed on renal impairment and in a mouse
IRI model, where it reduced mortality. Its pharmacological activity was most pronounced with combined dosing pre- and post-ischemia and weaker with either pre- or post-ischemia dosing alone. RMC-035 rapidly distributed to the kidneys via glomerular filtration and selective luminal uptake by proximal tubular cells.
IRI-induced expression of kidney heme oxygenase-1 was inhibited by RMC-035, consistent with its antioxidative properties. RMC-035 also dampened
IRI-associated inflammation and improved mitochondrial function, as shown by tubular autofluorescence. Taken together, the efficacy of RMC-035 is congruent with its targeted mechanism(s) and biodistribution profile, supporting its further clinical evaluation as a novel kidney-protective therapy.NEW & NOTEWORTHY A therapeutic A1M protein variant (RMC-035) is currently in phase 2 clinical development for renal protection in patients undergoing open-chest cardiac surgery. It targets several key pathways underlying kidney injury in this patient group, including oxidative stress, heme toxicity, and mitochondrial dysfunction. RMC-035 is rapidly eliminated from plasma, distributing to kidney proximal tubules, and demonstrates dose-dependent efficacy in numerous models of ischemia-reperfusion injury, particularly when administered before ischemia. These results support its continued clinical evaluation.