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

(2016) HEPATOLOGY. 63(4). p.1120-1134
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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.
Keywords
HCV ENTRY, BROADLY NEUTRALIZING ANTIBODIES, INFECTION IN-VIVO, LIVER-TRANSPLANTATION, E2 GLYCOPROTEIN, ANTIVIRAL ACTIVITY, TARGETING AGENTS, OPEN-LABEL, STRUCTURAL BASIS, ESCAPE

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Citation

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Chicago
Desombere, Isabelle, Samira Fafi-Kremer, Freya Van Houtte, Patrick Pessaux, Aliasghar Farhoudi Moghadam, Laura Heydmann, Lieven Verhoye, et al. 2016. “Monoclonal Anti-envelope Antibody AP33 Protects Humanized Mice Against a Patient-derived Hepatitis C Virus Challenge.” Hepatology 63 (4): 1120–1134.
APA
Desombere, Isabelle, Fafi-Kremer, S., Van Houtte, F., Pessaux, P., Farhoudi Moghadam, A., Heydmann, L., Verhoye, L., et al. (2016). Monoclonal anti-envelope antibody AP33 protects humanized mice against a patient-derived hepatitis C virus challenge. HEPATOLOGY, 63(4), 1120–1134.
Vancouver
1.
Desombere I, Fafi-Kremer S, Van Houtte F, Pessaux P, Farhoudi Moghadam A, Heydmann L, et al. Monoclonal anti-envelope antibody AP33 protects humanized mice against a patient-derived hepatitis C virus challenge. HEPATOLOGY. 2016;63(4):1120–34.
MLA
Desombere, Isabelle, Samira Fafi-Kremer, Freya Van Houtte, et al. “Monoclonal Anti-envelope Antibody AP33 Protects Humanized Mice Against a Patient-derived Hepatitis C Virus Challenge.” HEPATOLOGY 63.4 (2016): 1120–1134. Print.
@article{7143825,
  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.},
  author       = {Desombere, Isabelle and Fafi-Kremer, Samira and Van Houtte, Freya and Pessaux, Patrick and Farhoudi Moghadam, Aliasghar and Heydmann, Laura and Verhoye, Lieven and Cole, Sarah and McKeating, Jane A and Leroux-Roels, Geert and Baumert, Thomas F and Patel, Arvind H and Meuleman, Philip},
  issn         = {0270-9139},
  journal      = {HEPATOLOGY},
  language     = {eng},
  number       = {4},
  pages        = {1120--1134},
  title        = {Monoclonal anti-envelope antibody AP33 protects humanized mice against a patient-derived hepatitis C virus challenge},
  url          = {http://dx.doi.org/10.1002/hep.28428},
  volume       = {63},
  year         = {2016},
}

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