Human Monoclonal Antibody HCV1 Effectively Prevents and Treats HCV Infection in Chimpanzees

Trevor J. Morin, Teresa J. Broering, Brett A. Leav, Barbra M. Blair, Kirk J. Rowley, Elisabeth N. Boucher, Yang Wang, Peter S. Cheslock, Michael Knauber, David B. Olsen, Steve W. Ludmerer, G. Szabó, Robert W. Finberg, Robert H. Purcell, Robert E. Lanford, Donna M. Ambrosino, Deborah C. Molrine, Gregory J. Babcock

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

Hepatitis C virus (HCV) infection is a leading cause of liver transplantation and there is an urgent need to develop therapies to reduce rates of HCV infection of transplanted livers. Approved therapeutics for HCV are poorly tolerated and are of limited efficacy in this patient population. Human monoclonal antibody HCV1 recognizes a highly-conserved linear epitope of the HCV E2 envelope glycoprotein (amino acids 412-423) and neutralizes a broad range of HCV genotypes. In a chimpanzee model, a single dose of 250 mg/kg HCV1 delivered 30 minutes prior to infusion with genotype 1a H77 HCV provided complete protection from HCV infection, whereas a dose of 50 mg/kg HCV1 did not protect. In addition, an acutely-infected chimpanzee given 250 mg/kg HCV1 42 days following exposure to virus had a rapid reduction in viral load to below the limit of detection before rebounding 14 days later. The emergent virus displayed an E2 mutation (N415K/D) conferring resistance to HCV1 neutralization. Finally, three chronically HCV-infected chimpanzees were treated with a single dose of 40 mg/kg HCV1 and viral load was reduced to below the limit of detection for 21 days in one chimpanzee with rebounding virus displaying a resistance mutation (N417S). The other two chimpanzees had 0.5-1.0 log10 reductions in viral load without evidence of viral resistance to HCV1. In vitro testing using HCV pseudovirus (HCVpp) demonstrated that the sera from the poorly-responding chimpanzees inhibited the ability of HCV1 to neutralize HCVpp. Measurement of antibody responses in the chronically-infected chimpanzees implicated endogenous antibody to E2 and interference with HCV1 neutralization although other factors may also be responsible. These data suggest that human monoclonal antibody HCV1 may be an effective therapeutic for the prevention of graft infection in HCV-infected patients undergoing liver transplantation.

Original languageEnglish
Article numbere1002895
JournalPLoS Pathogens
Volume8
Issue number8
DOIs
Publication statusPublished - Aug 2012

Fingerprint

Pan troglodytes
Virus Diseases
Hepacivirus
Monoclonal Antibodies
Viral Load
Viruses
Liver Transplantation
Limit of Detection
Genotype
Mutation
Antibody Formation
Epitopes
Therapeutics
Transplants
Amino Acids
Antibodies
Liver

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Morin, T. J., Broering, T. J., Leav, B. A., Blair, B. M., Rowley, K. J., Boucher, E. N., ... Babcock, G. J. (2012). Human Monoclonal Antibody HCV1 Effectively Prevents and Treats HCV Infection in Chimpanzees. PLoS Pathogens, 8(8), [e1002895]. https://doi.org/10.1371/journal.ppat.1002895

Human Monoclonal Antibody HCV1 Effectively Prevents and Treats HCV Infection in Chimpanzees. / Morin, Trevor J.; Broering, Teresa J.; Leav, Brett A.; Blair, Barbra M.; Rowley, Kirk J.; Boucher, Elisabeth N.; Wang, Yang; Cheslock, Peter S.; Knauber, Michael; Olsen, David B.; Ludmerer, Steve W.; Szabó, G.; Finberg, Robert W.; Purcell, Robert H.; Lanford, Robert E.; Ambrosino, Donna M.; Molrine, Deborah C.; Babcock, Gregory J.

In: PLoS Pathogens, Vol. 8, No. 8, e1002895, 08.2012.

Research output: Contribution to journalArticle

Morin, TJ, Broering, TJ, Leav, BA, Blair, BM, Rowley, KJ, Boucher, EN, Wang, Y, Cheslock, PS, Knauber, M, Olsen, DB, Ludmerer, SW, Szabó, G, Finberg, RW, Purcell, RH, Lanford, RE, Ambrosino, DM, Molrine, DC & Babcock, GJ 2012, 'Human Monoclonal Antibody HCV1 Effectively Prevents and Treats HCV Infection in Chimpanzees', PLoS Pathogens, vol. 8, no. 8, e1002895. https://doi.org/10.1371/journal.ppat.1002895
Morin TJ, Broering TJ, Leav BA, Blair BM, Rowley KJ, Boucher EN et al. Human Monoclonal Antibody HCV1 Effectively Prevents and Treats HCV Infection in Chimpanzees. PLoS Pathogens. 2012 Aug;8(8). e1002895. https://doi.org/10.1371/journal.ppat.1002895
Morin, Trevor J. ; Broering, Teresa J. ; Leav, Brett A. ; Blair, Barbra M. ; Rowley, Kirk J. ; Boucher, Elisabeth N. ; Wang, Yang ; Cheslock, Peter S. ; Knauber, Michael ; Olsen, David B. ; Ludmerer, Steve W. ; Szabó, G. ; Finberg, Robert W. ; Purcell, Robert H. ; Lanford, Robert E. ; Ambrosino, Donna M. ; Molrine, Deborah C. ; Babcock, Gregory J. / Human Monoclonal Antibody HCV1 Effectively Prevents and Treats HCV Infection in Chimpanzees. In: PLoS Pathogens. 2012 ; Vol. 8, No. 8.
@article{7f6331b011694a05acd6ef3311dfb41f,
title = "Human Monoclonal Antibody HCV1 Effectively Prevents and Treats HCV Infection in Chimpanzees",
abstract = "Hepatitis C virus (HCV) infection is a leading cause of liver transplantation and there is an urgent need to develop therapies to reduce rates of HCV infection of transplanted livers. Approved therapeutics for HCV are poorly tolerated and are of limited efficacy in this patient population. Human monoclonal antibody HCV1 recognizes a highly-conserved linear epitope of the HCV E2 envelope glycoprotein (amino acids 412-423) and neutralizes a broad range of HCV genotypes. In a chimpanzee model, a single dose of 250 mg/kg HCV1 delivered 30 minutes prior to infusion with genotype 1a H77 HCV provided complete protection from HCV infection, whereas a dose of 50 mg/kg HCV1 did not protect. In addition, an acutely-infected chimpanzee given 250 mg/kg HCV1 42 days following exposure to virus had a rapid reduction in viral load to below the limit of detection before rebounding 14 days later. The emergent virus displayed an E2 mutation (N415K/D) conferring resistance to HCV1 neutralization. Finally, three chronically HCV-infected chimpanzees were treated with a single dose of 40 mg/kg HCV1 and viral load was reduced to below the limit of detection for 21 days in one chimpanzee with rebounding virus displaying a resistance mutation (N417S). The other two chimpanzees had 0.5-1.0 log10 reductions in viral load without evidence of viral resistance to HCV1. In vitro testing using HCV pseudovirus (HCVpp) demonstrated that the sera from the poorly-responding chimpanzees inhibited the ability of HCV1 to neutralize HCVpp. Measurement of antibody responses in the chronically-infected chimpanzees implicated endogenous antibody to E2 and interference with HCV1 neutralization although other factors may also be responsible. These data suggest that human monoclonal antibody HCV1 may be an effective therapeutic for the prevention of graft infection in HCV-infected patients undergoing liver transplantation.",
author = "Morin, {Trevor J.} and Broering, {Teresa J.} and Leav, {Brett A.} and Blair, {Barbra M.} and Rowley, {Kirk J.} and Boucher, {Elisabeth N.} and Yang Wang and Cheslock, {Peter S.} and Michael Knauber and Olsen, {David B.} and Ludmerer, {Steve W.} and G. Szab{\'o} and Finberg, {Robert W.} and Purcell, {Robert H.} and Lanford, {Robert E.} and Ambrosino, {Donna M.} and Molrine, {Deborah C.} and Babcock, {Gregory J.}",
year = "2012",
month = "8",
doi = "10.1371/journal.ppat.1002895",
language = "English",
volume = "8",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "8",

}

TY - JOUR

T1 - Human Monoclonal Antibody HCV1 Effectively Prevents and Treats HCV Infection in Chimpanzees

AU - Morin, Trevor J.

AU - Broering, Teresa J.

AU - Leav, Brett A.

AU - Blair, Barbra M.

AU - Rowley, Kirk J.

AU - Boucher, Elisabeth N.

AU - Wang, Yang

AU - Cheslock, Peter S.

AU - Knauber, Michael

AU - Olsen, David B.

AU - Ludmerer, Steve W.

AU - Szabó, G.

AU - Finberg, Robert W.

AU - Purcell, Robert H.

AU - Lanford, Robert E.

AU - Ambrosino, Donna M.

AU - Molrine, Deborah C.

AU - Babcock, Gregory J.

PY - 2012/8

Y1 - 2012/8

N2 - Hepatitis C virus (HCV) infection is a leading cause of liver transplantation and there is an urgent need to develop therapies to reduce rates of HCV infection of transplanted livers. Approved therapeutics for HCV are poorly tolerated and are of limited efficacy in this patient population. Human monoclonal antibody HCV1 recognizes a highly-conserved linear epitope of the HCV E2 envelope glycoprotein (amino acids 412-423) and neutralizes a broad range of HCV genotypes. In a chimpanzee model, a single dose of 250 mg/kg HCV1 delivered 30 minutes prior to infusion with genotype 1a H77 HCV provided complete protection from HCV infection, whereas a dose of 50 mg/kg HCV1 did not protect. In addition, an acutely-infected chimpanzee given 250 mg/kg HCV1 42 days following exposure to virus had a rapid reduction in viral load to below the limit of detection before rebounding 14 days later. The emergent virus displayed an E2 mutation (N415K/D) conferring resistance to HCV1 neutralization. Finally, three chronically HCV-infected chimpanzees were treated with a single dose of 40 mg/kg HCV1 and viral load was reduced to below the limit of detection for 21 days in one chimpanzee with rebounding virus displaying a resistance mutation (N417S). The other two chimpanzees had 0.5-1.0 log10 reductions in viral load without evidence of viral resistance to HCV1. In vitro testing using HCV pseudovirus (HCVpp) demonstrated that the sera from the poorly-responding chimpanzees inhibited the ability of HCV1 to neutralize HCVpp. Measurement of antibody responses in the chronically-infected chimpanzees implicated endogenous antibody to E2 and interference with HCV1 neutralization although other factors may also be responsible. These data suggest that human monoclonal antibody HCV1 may be an effective therapeutic for the prevention of graft infection in HCV-infected patients undergoing liver transplantation.

AB - Hepatitis C virus (HCV) infection is a leading cause of liver transplantation and there is an urgent need to develop therapies to reduce rates of HCV infection of transplanted livers. Approved therapeutics for HCV are poorly tolerated and are of limited efficacy in this patient population. Human monoclonal antibody HCV1 recognizes a highly-conserved linear epitope of the HCV E2 envelope glycoprotein (amino acids 412-423) and neutralizes a broad range of HCV genotypes. In a chimpanzee model, a single dose of 250 mg/kg HCV1 delivered 30 minutes prior to infusion with genotype 1a H77 HCV provided complete protection from HCV infection, whereas a dose of 50 mg/kg HCV1 did not protect. In addition, an acutely-infected chimpanzee given 250 mg/kg HCV1 42 days following exposure to virus had a rapid reduction in viral load to below the limit of detection before rebounding 14 days later. The emergent virus displayed an E2 mutation (N415K/D) conferring resistance to HCV1 neutralization. Finally, three chronically HCV-infected chimpanzees were treated with a single dose of 40 mg/kg HCV1 and viral load was reduced to below the limit of detection for 21 days in one chimpanzee with rebounding virus displaying a resistance mutation (N417S). The other two chimpanzees had 0.5-1.0 log10 reductions in viral load without evidence of viral resistance to HCV1. In vitro testing using HCV pseudovirus (HCVpp) demonstrated that the sera from the poorly-responding chimpanzees inhibited the ability of HCV1 to neutralize HCVpp. Measurement of antibody responses in the chronically-infected chimpanzees implicated endogenous antibody to E2 and interference with HCV1 neutralization although other factors may also be responsible. These data suggest that human monoclonal antibody HCV1 may be an effective therapeutic for the prevention of graft infection in HCV-infected patients undergoing liver transplantation.

UR - http://www.scopus.com/inward/record.url?scp=84866152584&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866152584&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1002895

DO - 10.1371/journal.ppat.1002895

M3 - Article

C2 - 22952447

AN - SCOPUS:84866152584

VL - 8

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 8

M1 - e1002895

ER -