Therapeutic alpha-1-microglobulin ameliorates kidney ischemia reperfusion injury.

Alpha-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 was assessed in various models of kidney ischemia and reperfusion injury (IRI). Real-time glomerular filtration rate, 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, also 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 shown by tubular autofluorescence. Taken together, the efficacy of RMC-035 is congruent with its targeted mechanism(s) and biodistribution profile and supports its further clinical evaluation as a novel kidney-protective therapy.