Safety and Efficacy of Avaren-Fc Lectibody Targeting HCV High-Mannose Glycans in a Human Liver Chimeric Mouse Model

Dent, Matthew; Hamorsky, Krystal; Vausselin, Thibaut; Dubuisson, Jean; Miyata, Yoshinari; Morikawa, Yoshio; Matoba, Nobuyuki

Background Infection with hepatitis C virus (HCV) remains to be a major cause of morbidity and mortality worldwide despite the recent advent of highly effective direct-acting antivirals. The envelope glycoproteins of HCV are heavily glycosylated with a high proportion of high-mannose glycans (HMGs), which serve as a shield against neutralizing antibodies and assist in the interaction with cell-entry receptors. However, there is no approved therapeutic targeting this potentially druggable biomarker. Methods The anti-HCV activity of AvFc was evaluated through the use of in vitro neutralization assays as well as an in vivo challenge in the PXB chimeric human liver mouse model. Drug toxicity was assessed by histopathology, serum ALT, and mouse body weights. Results AvFc was capable of neutralizing cell culture-derived HCV in a genotype-independent manner, with IC50 values in the low nanomolar range. Systemic administration of AvFc in a histidine-based buffer was well tolerated; after 11 doses every other day at 25 mg/kg there were no significant changes in body or liver weights or in blood human albumin or serum ALT activity. Gross necropsy and liver pathology confirmed the lack of toxicity. This regimen successfully prevented genotype 1a HCV infection in all animals, while an AvFc mutant lacking HMG binding activity failed. Conclusion These results suggest that targeting envelope HMGs is a promising therapeutic approach against HCV infection, and AvFc may provide a safe and efficacious means to prevent recurrent infection upon liver transplantation in HCV-related end-stage liver disease patients.