Preclinical evaluation of two neutralizing human monoclonal antibodies against hepatitis C virus (HCV): a potential treatment to prevent HCV reinfection in liver transplant patients.
Passive immunotherapy is potentially effective in preventing reinfection of liver grafts in hepatitis C virus (HCV)-associated liver transplant patients. A combination of monoclonal antibodies directed against different epitopes may be advantageous against a highly mutating virus such as HCV. Two human monoclonal antibodies (HumAbs) against the E2 envelope protein of HCV were developed and tested for the ability to neutralize the virus and prevent human liver infection. These antibodies, designated HCV-AB 68 and HCV-AB 65, recognize different conformational epitopes on E2. They were characterized in vitro biochemically and functionally. Both HumAbs are immunoglobulin G1 and have affinity constants to recombinant E2 constructs in the range of 10(-10) M. They are able to immunoprecipitate HCV particles from infected patients' sera from diverse genotypes and to stain HCV-infected human liver tissue. Both antibodies can fix complement and form immune complexes, but they do not activate complement-dependent or antibody-dependent cytotoxicity. Upon complement fixation, the monoclonal antibodies induce phagocytosis of the immune complexes by neutrophils, suggesting that the mechanism of viral clearance includes endocytosis. In vivo, in the HCV-Trimera model, both HumAbs were capable of inhibiting HCV infection of human liver fragments and of reducing the mean viral load in HCV-positive animals. The demonstrated neutralizing activities of HCV-AB 68 and HCV-AB 65 suggest that they have the potential to prevent reinfection in liver transplant patients and to serve as prophylactic treatment in postexposure events.
Eren
Rachel
R
XTL Biopharmaceuticals Ltd., Rehovot, Israel.
Landstein
Dorit
D
Terkieltaub
Dov
D
Nussbaum
Ofer
O
Zauberman
Arie
A
Ben-Porath
Judith
J
Gopher
Judith
J
Buchnick
Rachel
R
Kovjazin
Riva
R
Rosenthal-Galili
Ziva
Z
Aviel
Sigal
S
Ilan
Ehud
E
Shoshany
Yariv
Y
Neville
Lewis
L
Waisman
Tal
T
Ben-Moshe
Ofer
O
Kischitsky
Alberto
A
Foung
Steven K H
SK
Keck
Zhen-Yong
ZY
Pappo
Orit
O
Eid
Ahmed
A
Jurim
Oded
O
Zamir
Gidi
G
Galun
Eithan
E
Dagan
Shlomo
S
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000517:prevention & control*; D018937:Hepatitis C Antibodies / Q000627:therapeutic use*; D006801:Humans; D016031:Liver Transplantation / Q000009:adverse effects*; D051379:Mice; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D012008:Recurrence; D017422:Sequence Analysis, DNA; D014759:Viral Envelope Proteins / Q000276:immunology*
D000911:Antibodies, Monoclonal; D018937:Hepatitis C Antibodies; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus