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Targeting of oxidized Macrophage Migration Inhibitory Factor (oxMIF) with antibody ON104 attenuates the severity of
Maroua Ferhat1, Julia Mayer1, Lyndon H Costa2
1OncoOne Research & Development GmbH, Vienna, Austria.
Abstract:
The oxidized form of Macrophage Migration Inhibitory Factor (oxMIF) has been identified as the disease-related isoform of MIF, exerting pathological functions in inflamed tissue. In this study, we aimed to explore the in vivo effects of the neutralizing anti-oxMIF antibody ON104 in a rat model of crescentic glomerulonephritis (CGN), to better understand its disease modifying activities. WKY rats received a single intravenous injection of a rabbit nephrotoxic serum (NTS), targeting rat glomerular basement membrane to induce CGN. On day 4 and day 6, ON104 was given intraperitoneally (i.p.) and on day 8 urine, blood and kidney tissue were collected. ON104 substantially attenuated the severity of CGN demonstrated by reduced proteinuria, hematuria, as well as lower levels of kidney injury molecule (KIM)-1. ON104 treatment preserved the glomerular morphology and suppressed crescent formation, a hallmark of the disease. On the cellular level, oxMIF neutralization by ON104 strongly reduced the number of macrophages and neutrophils within the inflamed kidneys. In vitro, we identified human neutrophils, but not monocytes, as main producers of oxMIF among total peripheral cells. The present study demonstrates that oxMIF is a pertinent therapeutic target in a model of CGN which mechanistically resembles human immune mediated CGN. In this model, neutralization of oxMIF by ON104 leads to an improvement in both urinary abnormalities and histological pathological characteristics of the disease. ON104, thus has the potential to become a novel disease-modifying drug for the treatment of glomerulonephritis and other inflammatory kidney diseases.
Insights
The anti-oxidized Macrophage Migration Inhibitory Factor (oxMIF) antibody ON104 significantly reduced crescentic glomerulonephritis (CGN) severity in rats. ON104 improved kidney function and reduced inflammatory cells, showing potential as a novel treatment for glomerulonephritis.
Area of Science:
- Immunology
- Nephrology
- Pathology
Background:
- Oxidized Macrophage Migration Inhibitory Factor (oxMIF) is a disease-related isoform of MIF involved in inflammatory tissue damage.
- Macrophage Migration Inhibitory Factor (MIF) plays a critical role in immune responses and inflammation.
- Crescentic Glomerulonephritis (CGN) is a severe kidney disease characterized by rapid glomerular injury.
Purpose of the Study:
- To investigate the in vivo therapeutic effects of the neutralizing anti-oxMIF antibody ON104 in a rat model of CGN.
- To understand the disease-modifying activities of oxMIF neutralization in kidney inflammation.
- To identify the cellular sources of oxMIF in inflammatory conditions.
Main Methods:
- Induction of CGN in WKY rats using rabbit nephrotoxic serum (NTS).
- Administration of ON104 intraperitoneally on days 4 and 6 post-induction.
- Collection of urine, blood, and kidney tissue on day 8 for analysis.
- In vitro assessment of oxMIF production by human peripheral blood cells.
Main Results:
- ON104 treatment significantly attenuated CGN severity, reducing proteinuria, hematuria, and Kidney Injury Molecule (KIM)-1 levels.
- ON104 preserved glomerular morphology and suppressed crescent formation.
- Neutralization of oxMIF by ON104 decreased macrophage and neutrophil infiltration in inflamed kidneys.
- Human neutrophils were identified as major producers of oxMIF in vitro.
Conclusions:
- Oxidized Macrophage Migration Inhibitory Factor (oxMIF) is a viable therapeutic target in immune-mediated CGN.
- ON104 effectively neutralizes oxMIF, leading to improved urinary and histological outcomes in a rat CGN model.
- ON104 demonstrates potential as a novel disease-modifying drug for glomerulonephritis and other inflammatory kidney diseases.
