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Development and characterization of a human monoclonal antibody for prevention of HCV recurrence in liver transplant patients

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Abstract
More than 170 million people worldwide are chronically infected with hepatitis C virus (HCV) and are at risk of developing liver fibrosis, cirrhosis and hepatocellular carcinoma. Liver transplantation is the only option for patients with HCV-induced end-stage liver diseases. Nevertheless, infection of the newly grafted liver occurs immediately and universally after transplantation. Despite the recent progress in HCV therapy, a prophylactic vaccine is still not available. The role of neutralizing monoclonal antibodies (mAbs) in protection from different viral infections including HCV, HIV and Ebola has been reported. In the last few years, several mAbs with neutralizing activity have been described but only few mAbs have been evaluated in vivo. In the present study, we describe the development of a mAb, designated 2A5, isolated from HCV genotype 1b chronic patient. ELISA results indicated high affinity of mAb 2A5 towards HCV envelope glycoprotein (E1E2). The binding activity was completely lost against denatured E1E2 protein indicating that it targets a conformational epitope within the envelope region. Epitope mapping using alanine mutants of E1E2 proteins defined critical binding residues within the regions 419-447 and 612-617. Results of pseudoparticles (HCVpp) and cell culture produced virus (HCVcc) neutralization showed broad neutralizing activity of mAb 2A5 against all HCV genotypes. The efficacy study of mAb 2A5 in immune-deficient mice of which the liver is repopulated with human hepatocytes (humanized mice) showed complete protection from HCV challenge for genotypes 1a and 4a, while partial protection was achieved for genotypes 1b and 6a. Sequence analysis of E1E2 protein from non-protected mice did not revealed resistance mutations at interaction residues of mAb 2A5. In conclusion, mAb 2A5 shows potent anti-HCV neutralizing activity both in vitro and in vivo and could hence provide an effective strategy to prevent HCV recurrence in chronically infected HCV liver transplant patients. In addition, the broad neutralizing activity of this mAb presents a valuable epitope for the design of HCV vaccine with cross-protection activity.

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Chicago
Mesalam, Ahmed Atef Ahmed Abouzeid, Isabelle Desombere, Richard Urbanowicz, Daniel X Johansson, Koen Vercauteren, Aliasghar Farhoudi Moghadam, Freya Van Houtte, et al. 2017. “Development and Characterization of a Human Monoclonal Antibody for Prevention of HCV Recurrence in Liver Transplant Patients.” In IAP-VII Network HEPRO, International Symposium, Abstracts.
APA
Mesalam, A. A. A. A., Desombere, I., Urbanowicz, R., Johansson, D. X., Vercauteren, K., Farhoudi Moghadam, A., Van Houtte, F., et al. (2017). Development and characterization of a human monoclonal antibody for prevention of HCV recurrence in liver transplant patients. IAP-VII Network HEPRO, International symposium, Abstracts. Presented at the International symposium of the IAP-VII Network HEPRO: Liver disease and regeneration.
Vancouver
1.
Mesalam AAAA, Desombere I, Urbanowicz R, Johansson DX, Vercauteren K, Farhoudi Moghadam A, et al. Development and characterization of a human monoclonal antibody for prevention of HCV recurrence in liver transplant patients. IAP-VII Network HEPRO, International symposium, Abstracts. 2017.
MLA
Mesalam, Ahmed Atef Ahmed Abouzeid, Isabelle Desombere, Richard Urbanowicz, et al. “Development and Characterization of a Human Monoclonal Antibody for Prevention of HCV Recurrence in Liver Transplant Patients.” IAP-VII Network HEPRO, International Symposium, Abstracts. 2017. Print.
@inproceedings{8502442,
  abstract     = {More than 170 million people worldwide are chronically infected with hepatitis C virus (HCV) and are at risk of developing liver fibrosis, cirrhosis and hepatocellular carcinoma. Liver transplantation is the only option for patients with HCV-induced end-stage liver diseases. Nevertheless, infection of the newly grafted liver occurs immediately and universally after transplantation. Despite the recent progress in HCV therapy, a prophylactic vaccine is still not available. The role of neutralizing monoclonal antibodies (mAbs) in protection from different viral infections including HCV, HIV and Ebola has been reported. In the last few years, several mAbs with neutralizing activity have been described but only few mAbs have been evaluated in vivo. In the present study, we describe the development of a mAb, designated 2A5, isolated from HCV genotype 1b chronic patient. ELISA results indicated high affinity of mAb 2A5 towards HCV envelope glycoprotein (E1E2). The binding activity was completely lost against denatured E1E2 protein indicating that it targets a conformational epitope within the envelope region. Epitope mapping using alanine mutants of E1E2 proteins defined critical binding residues within the regions 419-447 and 612-617. Results of pseudoparticles (HCVpp) and cell culture produced virus (HCVcc) neutralization showed broad neutralizing activity of mAb 2A5 against all HCV genotypes. The efficacy study of mAb 2A5 in immune-deficient mice of which the liver is repopulated with human hepatocytes (humanized mice) showed complete protection from HCV challenge for genotypes 1a and 4a, while partial protection was achieved for genotypes 1b and 6a. Sequence analysis of E1E2 protein from non-protected mice did not revealed resistance mutations at interaction residues of mAb 2A5. In conclusion, mAb 2A5 shows potent anti-HCV neutralizing activity both in vitro and in vivo and could hence provide an effective strategy to prevent HCV recurrence in chronically infected HCV liver transplant patients. In addition, the broad neutralizing activity of this mAb presents a valuable epitope for the design of HCV vaccine with cross-protection activity. },
  author       = {Mesalam, Ahmed Atef Ahmed Abouzeid and Desombere, Isabelle and Urbanowicz, Richard  and Johansson, Daniel X and Vercauteren, Koen and Farhoudi Moghadam, Aliasghar and Van Houtte, Freya and Verhoye, Lieven and Persson, Mats and Ball, Jonathan and Leroux-Roels, Geert and Meuleman, Philip},
  booktitle    = {IAP-VII Network HEPRO, International symposium, Abstracts},
  language     = {eng},
  location     = {Leuven, Belgium},
  title        = {Development and characterization of a human monoclonal antibody for prevention of HCV recurrence in liver transplant patients},
  url          = {https://kuleuvencongres.be/heprosymposium},
  year         = {2017},
}