Abstract
Background & AimsInfection with hepatitis C virus (HCV) remains 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.MethodsThe anti-HCV activity of a fusion protein consisting of Avaren lectin and the fragment crystallizable (Fc) region of a human immunoglobulin G1 antibody, Avaren-Fc (AvFc) was evaluated through the use of in vitro neutralization assays as well as an in vivo challenge in a chimeric human liver (PXB) mouse model. Drug toxicity was assessed by histopathology, serum alanine aminotransferase, and mouse body weights.ResultsAvFc was capable of neutralizing cell culture–derived HCV in a genotype-independent manner, with 50% inhibitory concentration 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 alanine aminotransferase activity. Gross necropsy and liver pathology confirmed the lack of toxicity. This regimen successfully prevented genotype 1a HCV infection in all animals, although an AvFc mutant lacking HMG binding activity failed.ConclusionsThese 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.
Highlights
BACKGROUND & AIMSInfection with hepatitis C virus (HCV) CONCLUSIONS: These results suggest that targeting envelope remains a major cause of morbidity and mortality worldwide high-mannosetype N-glycans (HMGs) is a promising therapeutic approach against Hepatitis C virus (HCV) infec- despite the recent advent of highly effective direct-acting an- tion, and AvFc may provide a safe and efficacious means to tivirals
We previously described the development of an HMGtargeting lectin-Fc fusion protein, or lectibody, called
We found that AvFc has limited solubility in phosphate-buffered saline (PBS) at concentrations greater than 1 mg/mL
Summary
Infection with hepatitis C virus (HCV) CONCLUSIONS: These results suggest that targeting envelope remains a major cause of morbidity and mortality worldwide HMGs is a promising therapeutic approach against HCV infec- despite the recent advent of highly effective direct-acting an- tion, and AvFc may provide a safe and efficacious means to tivirals. The envelope glycoproteins of HCV are heavily glyco- prevent recurrent infection upon liver transplantation in HCV- sylated with a high proportion of high-mannose glycans related end-stage liver disease patients. (HMGs), which serve as a shield against neutralizing antibodies Hepatol and assist in the interaction with cell-entry receptors. There is no approved therapeutic targeting this potentially druggable biomarker
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