TY - JOUR
T1 - A novel neutralizing human monoclonal antibody broadly abrogates hepatitis C virus infection in vitro and in vivo
AU - Desombere, Isabelle
AU - Mesalam, Ahmed Atef
AU - Urbanowicz, Richard A
AU - Van Houtte, Freya
AU - Verhoye, Lieven
AU - Keck, Zhen-Yong
AU - Farhoudi, Ali
AU - Vercauteren, Koen
AU - Weening, Karin E
AU - Baumert, Thomas F
AU - Patel, Arvind H
AU - Foung, Steven K H
AU - Ball, Jonathan
AU - Leroux-Roels, Geert
AU - Meuleman, Philip
N1 - FTX; (CC BY 4.0)
PY - 2017
Y1 - 2017
N2 - Infections with hepatitis C virus (HCV) represent a worldwide health burden and a prophylactic vaccine is still not available. Liver transplantation (LT) is often the only option for patients with HCV-induced end-stage liver disease. However, immediately after transplantation, the liver graft becomes infected by circulating virus, resulting in accelerated progression of liver disease. Although the efficacy of HCV treatment using direct-acting antivirals has improved significantly, immune compromised LT-patients and patients with advanced liver disease remain difficult to treat. As an alternative approach, interfering with viral entry could prevent infection of the donor liver. We generated a human monoclonal antibody (mAb), designated 2A5, which targets the HCV envelope. The neutralizing activity of mAb 2A5 was assessed using multiple prototype and patient-derived HCV pseudoparticles (HCVpp), cell culture produced HCV (HCVcc), and a human-liver chimeric mouse model. Neutralization levels observed for mAb 2A5 were generally high and mostly superior to those obtained with AP33, a well-characterized HCV-neutralizing monoclonal antibody. Using humanized mice, complete protection was observed after genotype 1a and 4a HCV challenge, while only partial protection was achieved using gt1b and 6a isolates. Epitope mapping revealed that mAb 2A5 binding is conformation-dependent and identified the E2-region spanning amino acids 434 to 446 (epitope II) as the predominant contact domain.CONCLUSION: mAb 2A5 shows potent anti-HCV neutralizing activity both in vitro and in vivo and could hence represent a valuable candidate to prevent HCV recurrence in LT-patients. In addition, the detailed identification of the neutralizing epitope can be applied for the design of prophylactic HCV vaccines.
AB - Infections with hepatitis C virus (HCV) represent a worldwide health burden and a prophylactic vaccine is still not available. Liver transplantation (LT) is often the only option for patients with HCV-induced end-stage liver disease. However, immediately after transplantation, the liver graft becomes infected by circulating virus, resulting in accelerated progression of liver disease. Although the efficacy of HCV treatment using direct-acting antivirals has improved significantly, immune compromised LT-patients and patients with advanced liver disease remain difficult to treat. As an alternative approach, interfering with viral entry could prevent infection of the donor liver. We generated a human monoclonal antibody (mAb), designated 2A5, which targets the HCV envelope. The neutralizing activity of mAb 2A5 was assessed using multiple prototype and patient-derived HCV pseudoparticles (HCVpp), cell culture produced HCV (HCVcc), and a human-liver chimeric mouse model. Neutralization levels observed for mAb 2A5 were generally high and mostly superior to those obtained with AP33, a well-characterized HCV-neutralizing monoclonal antibody. Using humanized mice, complete protection was observed after genotype 1a and 4a HCV challenge, while only partial protection was achieved using gt1b and 6a isolates. Epitope mapping revealed that mAb 2A5 binding is conformation-dependent and identified the E2-region spanning amino acids 434 to 446 (epitope II) as the predominant contact domain.CONCLUSION: mAb 2A5 shows potent anti-HCV neutralizing activity both in vitro and in vivo and could hence represent a valuable candidate to prevent HCV recurrence in LT-patients. In addition, the detailed identification of the neutralizing epitope can be applied for the design of prophylactic HCV vaccines.
KW - Animals
KW - Antibodies, Monoclonal/immunology
KW - Antibodies, Neutralizing/immunology
KW - Disease Models, Animal
KW - Epitope Mapping
KW - Epitopes/genetics
KW - Genotype
KW - Hepacivirus/drug effects
KW - Hepatitis C/drug therapy
KW - Hepatitis C Antibodies/immunology
KW - Humans
KW - Liver Transplantation
KW - Mice
KW - Mice, SCID
KW - Mutation
KW - Neutralization Tests
KW - Structure-Activity Relationship
KW - Viral Envelope Proteins/genetics
KW - Virus Internalization/drug effects
U2 - 10.1016/j.antiviral.2017.10.015
DO - 10.1016/j.antiviral.2017.10.015
M3 - A1: Web of Science-article
C2 - 29074219
SN - 0166-3542
VL - 148
SP - 53
EP - 64
JO - Antiviral Research
JF - Antiviral Research
ER -