Investigation of Novel IgY Technology for Fungal Targets in Alcohol-associated Hepatitis

ABSTRACT Globally, 47% of liver-related deaths in 2016 were attributable to alcohol. Alcohol-associated hepatitis (AH), a severe form of alcohol-associated liver disease (ALD), is a major cause of liver-related morbidity and mortality worldwide. Currently, there are limited treatment options available, some of which are contraindicated, and none of which target the underlying mechanisms of disease. It has been shown that chronic alcohol consumption leads to gut dysbiosis, characterized by an overgrowth of pathogenic microbes and their toxins, which contribute to hepatic injury and inflammation, which are hallmarks of AH manifestation. Recent studies have implicated the fungus Candida albicans, and the toxin it produces, candidalysin, as a significant contributor to AH severity and mortality. This application proposes to develop a novel therapeutic approach developed by Prodigy Biotechnology using avian immunoglobulin Y (IgY) antibodies to selectively target and neutralize C. albicans and candidalysin. This completely novel drug modality leverages the unique properties of avian IgY antibodies obtained from hyperimmune chicken eggs, which can selectively target pathogenic microbes without disrupting beneficial gut flora or inducing adverse immune reactions. The study will first generate high-titer IgY antibodies against C. albicans and candidalysin and evaluate their neutralization capabilities in vitro (Aim 1). Next, Prodigy will conduct dose-ranging studies in a mouse model of chronic-binge ethanol-induced liver disease (Aim 2). Subsequently, the efficacy of the lead anti-C. albicans/candidalysin IgY product (Aims 3.1) and of the individual antibodies, anti- anti-C. albicans IgY and candidalysin IgY (Aim 3.2) will be assessed by measuring biomarkers of hepatic injury, steatosis, inflammation, intestinal permeability, dysbiosis, and microbial translocation. Significant reductions in these biomarkers are expected. Success in this study will support the development of an IgY product targeting multiple microbial drivers of AH to potentially improve disease outcomes and address a broader patient population than current medications. This approach could also establish IgY as a good research tool to understand the role of specific fungi in disease due to its specificity.