Department of Pharmacology and Toxicology.
Department of Medicine; James Graham Brown Cancer Center; Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, Kentucky.
Cell Mol Gastroenterol Hepatol. 2021;11(1):185-198. doi: 10.1016/j.jcmgh.2020.08.009. Epub 2020 Aug 27.
BACKGROUND & AIMS: Infection 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.
The 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.
AvFc 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.
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.
尽管近年来出现了高效的直接作用抗病毒药物，但丙型肝炎病毒 (HCV) 的感染仍然是全球发病率和死亡率的主要原因。HCV 的包膜糖蛋白高度糖基化，其中高甘露糖聚糖 (HMGs) 比例较高，它们作为中和抗体的屏蔽物，并有助于与细胞进入受体相互作用。然而，目前还没有针对这种潜在可用药标志物的批准治疗方法。
使用体外中和测定以及嵌合人肝 (PXB) 小鼠模型中的体内挑战，评估由 Avaren 凝集素和人免疫球蛋白 G1 抗体的 Fc 片段组成的融合蛋白 Avaren-Fc (AvFc) 的抗 HCV 活性。通过组织病理学、血清丙氨酸氨基转移酶和小鼠体重评估药物毒性。
AvFc 能够以基因型独立的方式中和细胞培养衍生的 HCV，半数抑制浓度值在低纳摩尔范围内。在基于组氨酸的缓冲液中系统给予 AvFc 可很好地耐受；在 25mg/kg 每隔一天给予 11 剂后，体重或肝脏重量、血液人白蛋白或血清丙氨酸氨基转移酶活性均无明显变化。大体尸检和肝脏病理学证实无毒性。该方案成功预防了所有动物的 1a 基因型 HCV 感染，尽管缺乏 HMG 结合活性的 AvFc 突变体则不行。
这些结果表明，针对包膜 HMGs 是一种有前途的 HCV 感染治疗方法，AvFc 可能为 HCV 相关终末期肝病患者肝移植后预防复发感染提供一种安全有效的手段。
