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.

Grant Number: 1R41AI191973-01
NIH Institute/Center: NIH
Principal Investigator: Satishchandran Chandrasekhar