#6547 ON104, A NOVEL BIOENGINEERED ANTIBODY TARGETING OXIDIZED MACROPHAGE MIGRATION INHIBITORY FACTOR (OXMIF) AMELIORATES EXPERIMENTAL GLOMERULONEPHRITIS

Abstract

Abstract Background and Aims Macrophage Migration Inhibitory Factor (MIF) is a pleiotropic inflammatory cytokine and a primary counter-regulator of glucocorticoids (GCs) that emerged as a pivotal regulator of immune-mediated disorders including glomerulonephritis (GN). MIF occurs in two immunologically distinct, conformational isoforms: reduced MIF, ubiquitously present in various tissues and the circulation of healthy subjects, and oxidized MIF (oxMIF), described as the pathogenic and druggable isoform of MIF [1]. We previously reported a positive correlation between disease severity and urinary oxMIF levels in patients with acute lupus nephritis, suggesting oxMIF contribution to kidney damage [2]. In this study we evaluated the anti-inflammatory effects of oxMIF neutralization using ON104 antibody during crescentic GN. Method By advanced antibody engineering we generated the fully human antibody ON104 that is specific and highly affine for human oxMIF and its orthologs. ON104 was tested for its therapeutic potential in a rodent model of GN. Nephritis was induced in male WKY rats by a single intravenous (i.v.) injection of rabbit anti-rat GBM (glomerular basement membrane) serum. On day 4 and day 6 after GN induction, ON104 was administrated intraperitoneally (i.p.). Body weight, proteinuria, and hematuria were assessed to evaluate GN severity. On day 8, kidneys were harvested for immuno-histological examinations by HE, PAS-staining and IHC staining. Results Treatment with ON104 substantially attenuated clinical signs of GN by preserving kidney function demonstrated by reduced proteinuria, and reduced hematuria. Furthermore, ON104 significantly reduced tissue injury, reduced crescentic glomerulus formation, and increased the percentage of normal glomeruli. On the cellular level, oxMIF neutralization by ON104 reduced CD68+ macrophage accumulation within the inflamed kidneys compared to untreated and isotype Ig-treated rats. Conclusion Our findings substantiate the role of oxMIF in the pathogenesis of experimental GN. Thus, targeting oxMIF may represent a new and promising treatment option for kidney diseases.