Abstract
Hepatitis C virus (HCV) is a major cause of chronic hepatitis and liver carcinoma and new therapies based on novel targets are needed. The tight junction protein claudin 1 (CLDN-1) is essential for HCV cell entry and spread, and anti-CLDN-1 rat and mouse mAbs are safe and effective in preventing and treating HCV infection in a human liver chimeric mouse model. To accelerate translation of these observations into a novel approach to treat HCV infection and disease in humans, we screened a phage display library of human single-chain antibody fragments by using a panel of CLDN-1-positive and -negative cell lines and identified phage specifically binding to CLDN-1. The 12 clones showing the highest levels of binding were converted into human IgG4. Some of these mAbs displayed low-nanomolar affinity, and inhibited infection of human hepatoma Huh7.5 cells by different HCV isolates in a dose-dependent manner. Cross-competition experiments identified six inhibitory mAbs that recognized distinct epitopes. Combination of the human anti-SRB1 mAb C-1671 with these anti-CLDN-1 mAbs could either increase or reduce inhibition of cell culture-derived HCV infection in vitro. These novel human anti-CLDN-1 mAbs are potentially useful to develop a new strategy for anti-HCV therapy and lend support to the combined use of antibodies targeting the HCV receptors CLDN-1 and SRB1, but indicate that care must be taken in selecting the proper combination.
Highlights
Hepatitis C virus (HCV) infection represents a major public health concern, with approximately 170 million people chronically infected (Dustin & Rice, 2007), resulting in about 470 000 deaths each year
HCV chronic infection leads to fibrosis, cirrhosis and liver carcinoma (50–76 % of all liver cancers), which are the primary reasons for liver transplantation (LT), and this is set to increase (Davis et al, 2003)
In the first selection scheme, we used human hepatoma Huh7.5 cells as antigen-positive cells, which naturally express high levels of claudin 1 (CLDN-1) as well as the other HCV receptors CD81 and SRB1. These cells were chosen because they can be infected by HCVs representative of different genotypes (Gottwein et al, 2009) and, represent a bona fide source of CLDN-1 displayed in the right conformation for HCV recognition and entry
Summary
Hepatitis C virus (HCV) infection represents a major public health concern, with approximately 170 million people chronically infected (Dustin & Rice, 2007), resulting in about 470 000 deaths each year. The mechanisms by which HCV escapes the immune response and establishes a chronic infection are not completely defined. HCV replicates at a high rate (Neumann et al, 1998) and its RNA-dependent RNA polymerase lacks proofreading capacity. This results in high genetic variability and rapid evolution under selection either by the immune system or in the presence of antiviral drugs. By early 2015, the US Food and Drug Administration and the European Medical
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