Monoclonal anti‐envelope antibody AP33 protects humanized mice against a patient‐derived hepatitis C virus challenge

Abstract

End-stage liver disease (ESLD) caused by hepatitis C virus (HCV) infection is a major indication for liver transplantation. However, immediately after transplantation, the liver graft of viremic patients universally becomes infected by circulating virus, resulting in accelerated liver disease progression. Currently available direct-acting antiviral therapies have reduced efficacy in patients with ESLD and prophylactic strategies to prevent HCV recurrence are still highly needed. In this study, we compared the ability of two broadly reactive monoclonal antibodies (mAbs), designated 3/11 and AP33, recognizing a distinct, but overlapping, epitope in the viral E2 glycoprotein to protect humanized mice from a patient-derived HCV challenge. Their neutralizing activity was assessed using the HCV pseudoparticles and cell-culture-derived HCV systems expressing multiple patient-derived envelopes and a human-liver chimeric mouse model. HCV RNA was readily detected in all control mice challenged with a patient-derived HCV genotype 1b isolate, whereas 3 of 4 AP33-treated mice were completely protected. In contrast, only one of four 3/11-treated mice remained HCV-RNA negative throughout the observation period, whereas the other 3 had a viral load that was indistinguishable from that in the control group. The increased in vivo efficacy of AP33 was in line with its higher affinity and neutralizing capacity observed in vitro. Conclusions: Although mAbs AP33 and 3/11 target the same region in E2, only mAb AP33 can efficiently protect from challenge with a heterologous HCV population in vivo. Given that mAb AP33 efficiently neutralizes viral variants that escaped the humoral immune response and reinfected the liver graft of transplant patients, it may be a valuable candidate to prevent HCV recurrence. In addition, our data are valuable for the design of a prophylactic vaccine. (HEPATOLOGY 2016;63:1120-1134

Altered Glycosylation Patterns Increase Immunogenicity of a Subunit Hepatitis C Virus Vaccine, Inducing Neutralizing Antibodies Which Confer Protection in Mice

“…A strong correlation between viral clearance and the induction of an early and broad NAb response following HCV infection has been reported in a number of patient cohorts with HCV infection (6)(7)(8). In addition, in vivo challenge/protection studies have shown that the passive transfer of monoclonal and polyclonal NAbs was able to prevent HCV infection in chimpanzees (9) and in mice (10)(11)(12)(13)(14), highlighting the important role of NAbs in protecting against HCV infection. A single HCV vaccine that could induce NAbs against all seven known HCV genotypes would be ideal.…”

Identification of a New Benzimidazole Derivative as an Antiviral against Hepatitis C Virus

“…The B5 treatment was initiated 4 days before the animals were challenged with serum-derived HCV and was continued for up to 31 days after injection of the virus. A similar pretreatment approach is usually used to characterize the antiviral activity of entry inhibitors in vivo (53)(54)(55)(56)(57). As shown in Fig.…”

Development and characterization of a human monoclonal antibody targeting the N-terminal region of hepatitis C virus envelope glycoprotein E1

“…The supernatant was collected and stored at −80 °C until use. Constructs containing the following viral strains were used: H77, UKN1A20.8, UKN1A14.38, J4, UKN1B5.23, UKN1B12.16, P5VD, P5VE, P5VF, JFH1, UKN2A1.2, UKN2B2.8, S52, UKN4.11.1, UKN5.14.4 and UKN6.5.8 in addition to 28 Belgian isolates (Desombere et al, 2016; Fafi-Kremer et al, 2010; Lavillette et al, 2005; Owsianka et al, 2005). …”

“…Polyclonal antibodies from HCV-infected patients were able to protect animal models like humanized mice and chimpanzees from HCV challenge (Bukh et al, 2015; Meuleman et al, 2011; Vanwolleghem et al, 2008). We and others previously reported that neutralizing antibodies targeting the E2 protein could protect from HCV infection in vitro and in vivo (Desombere et al, 2016; Keck et al, 2016; Mesalam et al, 2016). In addition, administration of mAb MBL-HCV1, targeting E2, delayed viral rebound following liver transplantation, while complete protection was reported when combined with the polymerase inhibitor sofosbuvir (Chung et al, 2013; Smith et al, 2017).…”